Molecular Mechanisms and Clinical Implications of Fibroblast Growth Factor Receptor 2 Signaling in Gastrointestinal Stromal Tumors

Round 1

Reviewer 1 Report (New Reviewer)

Comments and Suggestions for Authors

Dear Authors,

The article «Molecular Mechanisms and Clinical Implications of FGFR2 in Gastrointestinal Stromal Tumors» is a review focusing on the role of FGFR2 mutations in the resistance to TKI.

 

1. In the Title the abbreviation FGFR2 needs to be spelled out. KIT or PDGFRA in the Introduction section need to be spelled out also. Please, look through the text.
2. What are the other molecular mechanisms besides mutations which contribute to the resistance to Please, discuss this issue.
3. The expression profile of FGFR2 in general and particularly in Gastrointestinal Stromal Tumors should be mentioned
4. Is the any clinically significant polymorphisms of FGFR2? Please, discuss this issue
5. It is desirable to give the numbers (%) of the frequencies of different mutations FGFR2 leading to TKI resistance
6. Table 6. Is not noted in the text. The name is too general “Identified studies on GlST”. Please, name it more specifically.

PFS, OS need to be spelled out. The table needs improvement. For example, “Standard in 4th line” is the Key Findings. What does it mean?

7. Tables 2, 3, 4, 5, and 6 are not referenced in the preceding text. Introductory phrases explaining their purpose should be added.
8. Gene names should be written in italics.

 

Author Response

Responses to Reviewer 1

We thank Reviewer 1 for the insightful comments that have helped us improve the manuscript's precision and completeness.

Comment 1: In the Title the abbreviation FGFR2 needs to be spelled out.

Response: We agree completely. The title has been revised to spell out the full name of the gene.

Revision: The title now reads: "Molecular Mechanisms and Clinical Implications of Fibroblast Growth Factor Receptor 2 in Gastrointestinal Stromal Tumors.

Comment 2: KIT or PDGFRA in the Introduction section need to be spelled out also. Please, look through the text.

Response: Thank you for this suggestion. We have carefully reviewed the entire manuscript to ensure that all gene names and abbreviations, including KIT and PDGFRA, are spelled out upon their first mention and used consistently thereafter.

Revision: The Introduction now states: "...activating mutations in either the KIT (KIT proto-oncogene receptor tyrosine kinase) gene or the PDGFRA (platelet-derived growth factor receptor alpha) gene...". We have applied this principle throughout the text.

Comment 3: What are the other molecular mechanisms besides mutations which contribute to the resistance? Please, discuss this issue.

Response: This is an excellent point. We have expanded the Introduction to include a discussion of non-mutational mechanisms that contribute to FGFR2-mediated resistance.

Revision: A new paragraph has been added to the Introduction to address this, covering mechanisms such as "gene amplification leading to receptor overexpression, ligand overexpression (e.g., FGF7 and FGF10) driving autocrine or paracrine activation, bypass signaling that circumvents KIT and PDGFRA inhibition, and tumor microenvironmental interactions".

Comment 4: The expression profile of FGFR2 in general and particularly in Gastrointestinal Stromal Tumors should be mentioned.

Response: We appreciate this suggestion to enhance the biological context. We have added a new subsection to discuss the expression profile of FGFR2.

Revision: A new subsection, "3.1.3. Physiological and Pathological Relevance", has been created. It discusses FGFR2 expression in normal epithelial and mesenchymal tissues and its variable expression levels in GISTs, particularly in tumors lacking canonical driver mutations.

Comment 5: Is there any clinically significant polymorphisms of FGFR2? Please, discuss this issue.

Response: Thank you for raising this important topic. We have clarified the role of polymorphisms in the manuscript and added this information to a summary table.

Revision: We now state in the Abstract that "clinically significant polymorphisms are extremely rare". We have also added a dedicated row for "Polymorphisms" in the revised

Table 2, noting that while they are reported in other cancers, their association with GIST has not been established and requires further investigation.

Comment 6: It is desirable to give the numbers (%) of the frequencies of different mutations FGFR2 leading to TKI resistance.

Response: We agree that providing specific frequencies enhances the manuscript's precision. We have updated the text with the most current data on the prevalence of different FGFR2 alteration types.

Revision: The Abstract and main text (Section 3.2.1) have been revised to provide specific frequencies: "approximately 1–2% of GIST cases, most commonly as gene fusions (e.g., FGFR2::TACC2, <1%) or amplifications (1–2%)". Point mutations are now correctly cited as being "extremely uncommon (<0.1%)". This information is also summarized in the new Table 2.

Comment 7: Table 6. Is not noted in the text. The name is too general “Identified studies on GlST”. Please, name it more specifically. PFS, OS need to be spelled out. The table needs improvement. For example, “Standard in 4th line” is the Key Findings. What does it mean?

Response: We appreciate this detailed feedback and have completely overhauled Table 6 to improve its clarity, specificity, and relevance.

Revision:

Title and Relevance: The table has been retitled and its content focused specifically on studies relevant to FGFR2-altered GISTs, with historical benchmark trials included for context.

Clarity: The confusing entry "Standard in 4th line" has been replaced with a specific finding from the INVICTUS trial: "PFS 6.3 mo vs 1.0 mo; OS HR 0.36 ".

Abbreviations: The abbreviations for Progression-Free Survival (PFS) and Overall Survival (OS) have been spelled out in the main abbreviations list.

Citation: The table is now properly introduced and cited in the text.

Comment 8: Tables 2, 3, 4, 5, and 6 are not referenced in the preceding text. Introductory phrases explaining their purpose should be added.

Response: Thank you for noting this oversight. We have revised the text to ensure that every table is introduced with an explanatory sentence and is appropriately cited in the narrative that precedes it.

Revision: For example, the text now includes phrases like, "The approximate frequencies, molecular features, and clinical implications of FGFR2 alterations in GISTs are summarized in Table 2" and "The mutual exclusivity of

FGFR2 with KIT/PDGFRA mutations has three major clinical implications, summarised in Table 5". This has been done for all tables.

Comment 9: Gene names should be written in italics.

Response: We agree and have corrected this throughout the manuscript.

Revision: All gene names (e.g., FGFR2, KIT, PDGFRA, TACC2) have been italicized in accordance with scientific publishing standards.

 

Reviewer 2 Report (New Reviewer)

Comments and Suggestions for Authors

The article reviews the role of FGFR2 in the pathogenesis, resistance mechanisms, and therapeutic potential in GISTs, particularly in cases resistant to tyrosine kinase inhibitors (TKIs) like imatinib.

The review article is novel, it comprehensively covers the role of FGFR2 in GISTs, with integration of molecular and clinical data, and emphasis on therapeutic implications

 

The review article is well-written and organized, figures and tables are clear, enhancing the article's readability, and the references are relevant and updated

However,

• Minor typographical errors (e.g., "h4ps" instead of "https") should be corrected.
• “KIT” should be mentioned in full name upon first mention

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This review highlights the significant yet underappreciated role of FGFR2 gene alterations in driving Gastrointestinal Stromal Tumors (GISTs), particularly those resistant to standard tyrosine kinase inhibitors (TKIs). While most GISTs are driven by KIT or PDGFRA mutations, this work establishes FGFR2 as a key alternative oncogenic driver and mechanism of TKI resistance, especially in wild-type tumors. Furthermore, the review article explores the therapeutic potential of FGFR inhibitors (e.g., erdafitinib, pemigatinib) as a novel approach in FGFR2-altered GISTs. It discusses combination therapies, such as FGFR inhibitors with TKIs or DNA-damaging agents, to overcome resistance mechanisms—a strategy that has not been widely studied in GISTs.
The authors not only summarize literature; they also effectively bridge basic science and clinical practice. They provided a critical evaluation via identifying and rectifying previous misconceptions such as the overstatement of FGFR2 point mutations in GIST and highlighted the limitations of current evidence, such as small sample sizes and the reliance on data from other cancers.

The review article effectively bridges basic science and clinical practice. They provided a critical evaluation via identifying and rectifying previous misconceptions such as the overstatement of FGFR2 point mutations in GIST and highlighted the limitations of current evidence, such as small sample sizes and the reliance on data from other cancers.
The manuscript is scientifically sound, logically organized, structured with clear headings and subheadings, and is clearly written. No improvements are required.
The conclusion is consistent with provided evidence.  It makes a valuable scientific  contribution by moving the focus beyond the canonical KIT/PDGFRA paradigm and highlighting the importance of comprehensive molecular profiling for personalized therapy
References are relevant and the use of tables and a conceptual figure is appropriate for a review article.

Author Response

Responses to Reviewer 2

We thank Reviewer 2 for the positive and encouraging feedback, as well as for pointing out areas for minor corrections.

Comment 1: Minor typographical errors (e.g., "h4ps" instead of "https") should be corrected.

Response: We appreciate the reviewer pointing this out. The entire manuscript has been carefully proofread to correct all typographical, grammatical, and formatting errors.

Revision: We have corrected the specific error mentioned and performed a thorough language polish of the entire document.

Comment 2: “KIT” should be mentioned in full name upon first mention.

Response: Thank you. As noted in our response to Reviewer 1, we have ensured that KIT and all other key abbreviations are fully defined upon their first appearance in the text.

Revision: The full name, KIT proto-oncogene receptor tyrosine kinase, is provided at its first use in the Introduction.

Reviewer 3 Report (New Reviewer)

Comments and Suggestions for Authors

Scientific Comments:

1. The manuscript covers FGFR2 biology well, but much of the discussion relies on extrapolated evidence from other cancers; more distinction between GIST-specific data and indirect evidence would improve accuracy.
2. The prevalence of FGFR2 alterations in GIST (1–2%) is repeatedly cited, but these numbers are based on small cohorts; a critical assessment of their reliability and population variability would be valuable.
3. The discussion of FGFR2 and DNA damage repair is interesting, though evidence in GIST remains speculative; it would help to clarify that most supporting data come from other cancers.
4. The concept of mutual exclusivity with KIT/PDGFRA mutations is presented clearly, but rare reports of co-occurrence deserve more critical consideration regarding their clinical impact.
5. Clinical trial data referenced are primarily from basket trials or case reports; it should be emphasized that GIST-specific phase II/III trials of FGFR2 inhibitors are still lacking.
6. While bypass signaling via FGFR2 is described, the review does not fully evaluate whether FGFR2 alone is sufficient for resistance or whether other factors, such as the tumor microenvironment, are involved.
7. Isoform-specific roles of FGFR2b and FGFR2c are mentioned, but their relevance to GISTs derived from mesenchymal cells could be elaborated further to strengthen mechanistic insights.
8. The conclusions could more explicitly highlight the need for experimental models (e.g., FGFR2-driven GIST cell lines, xenografts, CRISPR systems) to validate hypotheses raised in the review.

 

Technical Comments:

1. The statement about FGFR2 alterations occurring in 1–2% of GISTs and their exclusivity with KIT/PDGFRA is repeated many times; condensing this information would improve readability.
2. Figures are useful but their legends are too brief; adding explanatory details would make them more self-contained and educational.
3. Tables are informative but not always referenced clearly in the main text; stronger integration into the narrative would improve flow.
4. The description of the literature search lacks transparency on numbers screened and included; a PRISMA-style diagram or quantitative summary would add rigor.
5. The writing is generally clear but contains minor grammatical issues and awkward phrasing (e.g., “the keyword” instead of “keywords”); careful language polishing is needed.
6. The references contain typographical and formatting errors (e.g., “a ributable” instead of “attributable”); consistent editing across the manuscript is required.

Author Response

Responses to Reviewer 3

We are grateful to Reviewer 3 for the deep and critical scientific and technical comments, which have substantially improved the manuscript's rigor and nuance.

Scientific Comments:

Comment 1 & 3: The manuscript covers FGFR2 biology well, but much of the discussion relies on extrapolated evidence from other cancers; more distinction between GIST-specific data and indirect evidence would improve accuracy. The discussion of FGFR2 and DNA damage repair is interesting, though evidence in GIST remains speculative; it would help to clarify that most supporting data come from other cancers.

Response: This is a crucial point. We have meticulously revised the manuscript to clearly distinguish between direct GIST-specific evidence and data extrapolated from other malignancies.

Revision: We have added explicit clarifying statements in multiple sections. For example, in Section 3.1.2, we state, "...while these mechanisms are well established in... other cancers...

direct evidence in GIST remains limited...". Similarly, the critical evaluation of DNA damage repair (Section 3.4.5) now emphasizes, "

Current studies rely heavily on analogies from other FGFR-driven cancers, with limited GIST-specific data...".

Comment 2: The prevalence of FGFR2 alterations in GIST (1–2%) is repeatedly cited, but these numbers are based on small cohorts; a critical assessment of their reliability and population variability would be valuable.

Response: We acknowledge this limitation. We have added text to critically assess the reliability of the cited prevalence figures.

Revision: We now explicitly state that the estimated 1–2% frequency is "...based on targeted sequencing and next-generation sequencing (NGS) studies in small cohorts". Critical evaluation sections (e.g., Section 4.1.4) also highlight that the low incidence "limits large-scale clinical data; most evidence derives from small cohorts or case reports".

Comment 4: The concept of mutual exclusivity with KIT/PDGFRA mutations is presented clearly, but rare reports of co-occurrence deserve more critical consideration regarding their clinical impact.

Response: Thank you for this suggestion. We have expanded our discussion on the exceptions to mutual exclusivity.

Revision: In Section 4.2.1, we now discuss rare cases of co-occurrence, proposing that they "likely represent secondary resistance via subclonal evolution rather than true co-driver status, supported by single-cell sequencing showing distinct mutation-bearing populations".

Comment 5: Clinical trial data referenced are primarily from basket trials or case reports; it should be emphasized that GIST-specific phase II/III trials of FGFR2 inhibitors are still lacking.

Response: We agree this is an important distinction to make. We have revised the Discussion to be more precise about the source of clinical data and future needs.

Revision: The Discussion section now clarifies that "Evidence to date is largely extrapolated from basket trialsdesigned for cholangiocarcinoma or urothelial carcinoma" and highlights the need for dedicated trials, mentioning the planned "

global, multicentre phase II trial (PEMIGIST-2; planned N = 50)" which will be GIST-specific.

Comment 6: While bypass signaling via FGFR2 is described, the review does not fully evaluate whether FGFR2 alone is sufficient for resistance or whether other factors, such as the tumor microenvironment, are involved.

Response: This is a valuable insight. We have now incorporated the role of the tumor microenvironment into our discussion of resistance mechanisms.

Revision: The Introduction now includes "tumor microenvironmental interactions that promote tumor survival under therapeutic pressure" as a contributing mechanism. Figure 1 has also been updated to include "Tumor microenvironment remodeling" as a functional outcome.

Comment 7: Isoform-specific roles of FGFR2b and FGFR2c are mentioned, but their relevance to GISTs derived from mesenchymal cells could be elaborated further to strengthen mechanistic insights.

Response: Thank you for this suggestion. We have expanded the section on FGFR2 structure to elaborate on the specific relevance of the FGFR2c isoform to GISTs.

Revision: Section 3.1 now clarifies that "FGFR2c is the predominant isoform expressed in mesenchymal-derived cells, including the interstitial cells of Cajal... Consequently, FGFR2c is more likely to be functionally relevant in GISTs...".

Comment 8: The conclusions could more explicitly highlight the need for experimental models (e.g., FGFR2-driven GIST cell lines, xenografts, CRISPR systems) to validate hypotheses raised in the review.

Response: We agree. The need for better preclinical models is a critical next step for the field.

Revision: The Conclusion now explicitly recommends that "Future research should prioritize... development of FGFR2-driven models..." to validate FGFR2 as a therapeutic target. The Discussion section also highlights this need.

Round 2

Reviewer 1 Report (New Reviewer)

Comments and Suggestions for Authors

Dear Authors,

The title of the article is not correct, since the clinical implication of the receptor can not be.

My proposal " Molecular Mechanisms and Clinical Implications of FGFR2 signaling in Gastrointestinal Stromal Tumors" or other more variants

 

Author Response

Comment 1: The title of the article is not correct, since the clinical implication of the receptor can not be. My proposal " Molecular Mechanisms and Clinical Implications of FGFR2 signaling in Gastrointestinal Stromal Tumors" or other more variants.

Response1: Thank you for your detailed recommendation. We changed the title to："Molecular Mechanisms and Clinical Implications of Fibroblast Growth Factor Receptor 2 signaling in Gastrointestinal Stromal Tumors".

Reviewer 3 Report (New Reviewer)

Comments and Suggestions for Authors

The manuscript has been carefully revised and I am satisfied with the current version. The results are now clearly presented, and the figures have been appropriately updated according to the earlier suggestions. Overall, the revisions are adequate, and I recommend acceptance of the manuscript in its present form.

Author Response

Comment 1: The manuscript has been carefully revised and I am satisfied with the current version. The results are now clearly presented, and the figures have been appropriately updated according to the earlier suggestions. Overall, the revisions are adequate, and I recommend acceptance of the manuscript in its present form.

Response: We would like to express our heartfelt gratitude to all the reviewers for their hard work. I am also very honored to receive their positive feedback and recognition. Thank you all again.

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript titled "Molecular Mechanisms and Clinical Implications of FGFR2 in 2 Gastrointestinal Stromal Tumors" presents the role of fibroblast growth factor receptor 2 (FGFR2) in the pathogenesis and treatment of gastrointestinal stromal tumors (GISTs). It focuses on FGFR2 gene alterations, their involvement in signaling pathways, drug resistance, and potential as a therapeutic target. Understanding FGFR2 in GIST offers new insights into tumor biology beyond common KIT and PDGFRA mutations. I would like to thank the authors for their efforts and kindly request that they revise the review grammatically. And I recommend accepting the review

1. The abstract should be revised grammatically.
2. The keywords should be arranged alphabetically.
3. The whole review should avoid the repetition of words that have the same meaning, and simple grammatical mistakes.

Author Response

Comment 1: The abstract should be revised grammatically.

Response: We acknowledge the need to improve the grammatical accuracy of the abstract to ensure it is clear, concise, and professionally polished. In the original manuscript, the abstract contained minor grammatical issues, such as awkward phrasing (e.g., “Research on its pathogenesis and treatment strategies has remained a major focus”) and inconsistent sentence structures, which could affect readability. To address this, we have undertaken a comprehensive revision of the abstract, focusing on the following improvements:

• Grammatical Corrections: We corrected subject-verb agreement errors, improved sentence flow, and ensured consistent tense usage (e.g., changing “has remained” to “remains” for present relevance). For example, the sentence “With the in-depth study of GIST, the role of the fibroblast growth factor receptor 2 (FGFR2) gene in its pathogenesis has gradually gained attention” was revised to “Recent studies have highlighted the emerging role of fibroblast growth factor receptor 2 (FGFR2) in GIST pathogenesis” to enhance clarity and conciseness.
• Structural Enhancement: Following Reviewer 2’s suggestion, we restructured the abstract into five distinct sections (Introduction, Aim, Methods, Results, Conclusion) to improve logical flow and readability. This structure ensures that each sentence serves a specific purpose, reducing redundancy and enhancing grammatical coherence.
• Specific Examples: To make the abstract more engaging, we included specific examples, such as FGFR2::TACC2 fusions and FGFR inhibitors (e.g., erdafitinib, pemigatinib), ensuring precise terminology and avoiding vague phrases. For instance, “potential value in tumor resistance mechanisms” was revised to “contribution to tyrosine kinase inhibitor (TKI) resistance,” aligning with standard scientific language.
• Professional Editing: The revised abstract was reviewed by a professional language editing service (Editage, acknowledged in the manuscript) to ensure grammatical accuracy, polished style, and adherence to academic writing conventions.

The revised abstract now reads as follows (example excerpt, full text in manuscript):

Abstract
Introduction: Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms driven by KIT or PDGFRA mutations, but fibroblast growth factor receptor 2 (FGFR2) alterations are emerging as key oncogenic drivers in specific subtypes. Aim: This review synthesizes the molecular mechanisms and clinical implications of FGFR2 in GISTs, focusing on its role in pathogenesis, drug resistance, and therapeutic potential. Methods: We systematically reviewed peer-reviewed studies on FGFR2 in GISTs, integrating molecular pathology and clinical data. Results: FGFR2 alterations, including FGFR2::TACC2 fusions and amplifications, activate MAPK/ERK and PI3K/AKT pathways, promoting tumor proliferation and TKI resistance. FGFR inhibitors, such as erdafitinib, show promise in FGFR2-driven GISTs. Conclusion: FGFR2 is a critical biomarker for precision oncology in GISTs, warranting further research into targeted therapies.
Keywords: FGFR2 gene, gastrointestinal stromal tumor, gene fusion, molecular diagnosis, signaling pathway, targeted therapy, tyrosine kinase inhibitor.

These revisions improve the abstract’s grammatical accuracy, clarity, and scientific precision, making it an effective summary of the review’s scope and findings.
Location in Revised Manuscript: Abstract section, page 1, first paragraph, highlighted in track changes.
Contribution to Manuscript: The polished abstract enhances the manuscript’s first impression, ensuring it is accessible to a broad readership and accurately reflects the review’s scientific rigor.

Comment 2: The keywords should be arranged alphabetically.

Response: We appreciate your suggestion to organize the keywords alphabetically, as this improves accessibility and aligns with standard publication practices. In the original manuscript, the keywords (“gastrointestinal stromal tumor; FGFR2 gene; gene fusion; signaling pathway; drug resistance; molecular diagnosis; targeted therapy”) were listed without a consistent order, which could make it harder for readers to quickly identify relevant terms. To address this, we have revised the keywords section as follows:

• Alphabetical Reordering: The keywords have been rearranged in alphabetical order: “FGFR2 gene, fibroblast growth factor receptor 2, gastrointestinal stromal tumor, gene fusion, molecular diagnosis, signaling pathway, targeted therapy, tyrosine kinase inhibitor.”
• Keyword Refinement: We added “fibroblast growth factor receptor 2” as a full-term keyword to ensure clarity for readers unfamiliar with the abbreviation “FGFR2” and included “tyrosine kinase inhibitor” to reflect the review’s focus on TKI resistance, a key theme highlighted in Sections 2.3 and 2.7. This ensures the keywords comprehensively cover the manuscript’s content.
• Consistency Check: We verified that all keywords are consistently used in the manuscript and align with the terminology in the abstract and main text (e.g., “gastrointestinal stromal tumor” is uniformly abbreviated as “GIST” after first mention).

The revised keywords section now reads:

Keywords: FGFR2 gene, fibroblast growth factor receptor 2, gastrointestinal stromal tumor, gene fusion, molecular diagnosis, signaling pathway, targeted therapy, tyrosine kinase inhibitor.

This revision enhances the manuscript’s discoverability in database searches and ensures the keywords are reader-friendly and representative of the review’s scope.
Location in Revised Manuscript: Abstract section, page 1, immediately following the abstract text, highlighted in track changes.
Contribution to Manuscript: Alphabetized keywords improve the manuscript’s indexing and accessibility, facilitating its use by researchers and clinicians searching for FGFR2-related topics in GISTs.

Comment 3: The whole review should avoid the repetition of words that have the same meaning, and simple grammatical mistakes.

Response: We fully agree that eliminating repetitive phrasing and correcting grammatical errors is essential for improving the manuscript’s readability and professionalism. In the original manuscript, repetitive use of terms like “important,” “crucial,” and “promote” (e.g., in Sections 2.1 and 2.2) and minor grammatical issues (e.g., inconsistent tense, misplaced modifiers) detracted from the narrative flow. We have addressed this comment through a systematic approach, detailed below:

• Eliminating Repetition:
  • Synonym Variation: We conducted a word frequency analysis to identify overused terms and replaced them with synonyms to diversify the language. For example, in Section 2.1.1, repeated uses of “important” were replaced with “significant,” “pivotal,” or “notable” (e.g., “important biomarker” → “significant biomarker”). In Section 2.2.2, “promotes tumor growth” was varied with “drives tumor progression” or “enhances oncogenesis” to reduce monotony.
  • Sentence Restructuring: Redundant phrases were consolidated. For instance, in Section 2.3.1, the original text repeated “FGFR2::TACC2 fusion promotes tumor cell proliferation and survival.” This was revised to a single, concise statement: “FGFR2::TACC2 fusion activates MAPK/ERK pathways, driving tumor proliferation and survival” [Shi et al., 51], combining related ideas to avoid reiteration.
  • Section-Specific Examples:
    • In Section 2.2.1, repetitive mentions of “FGFR2 overexpression correlates with malignancy” were streamlined by summarizing the correlation once and elaborating on specific outcomes (e.g., “linked to poor prognosis and increased invasiveness”).
    • In Section 2.7, repeated references to “therapeutic potential” were replaced with terms like “clinical applicability” or “treatment efficacy” to maintain reader engagement.
  • Correcting Grammatical Mistakes:
    • Tense Consistency: We ensured consistent use of present tense for general statements (e.g., “FGFR2 plays a role” instead of “has played”) and past tense for specific study findings (e.g., “Shi et al. reported…”). For example, in Section 2.1.2, “FGFR2 mutations were found to be closely related” was revised to “FGFR2 alterations are associated with…” for present relevance.
    • Sentence Clarity: Misplaced modifiers and unclear pronoun references were corrected. In Section 2.4.1, the original phrase “it enhances RAD51 recruitment” was clarified to “FGFR2 enhances RAD51 recruitment” to avoid ambiguity.
    • Punctuation and Syntax: We corrected punctuation errors (e.g., missing Oxford commas in lists) and improved sentence syntax for flow. For example, in Section 2.5.1, the original “Tissue biopsy, which is an invasive method, it provides…” was revised to “Tissue biopsy, an invasive method, provides comprehensive molecular data…” to eliminate incorrect pronoun usage.
    • Professional Editing: The entire manuscript was reviewed by Editage, a professional language editing service, to ensure grammatical accuracy and stylistic consistency. Specific errors, such as subject-verb agreement (e.g., “Studies has shown” corrected to “Studies have shown” in Section 2.6), were addressed systematically.
  • Quality Assurance:
    • To ensure thoroughness, we used grammar-checking tools (e.g., Grammarly) as a preliminary step, followed this with manual review by two co-authors to catch nuanced errors.
    • We paid special attention to sections with dense scientific content (e.g., Sections 2.3 and 2.6), where repetition of technical terms was more likely, and ensured varied phrasing without compromising accuracy.
    • The revised text was cross-checked against the original manuscript to confirm that no new errors were introduced during editing.

Example Revision (Section 2.2.2, Original vs. Revised):

• Original: “Activation of FGFR2 is important for tumor development. FGFR2 gene fusion is an important mechanism that promotes tumor growth by activating important signaling pathways like PI3K/AKT. It is also important because it promotes survival.”
• Revised: “FGFR2 activation drives tumorigenesis through distinct mechanisms. FGFR2::TACC2 fusions enhance MAPK/ERK signaling, fostering cell proliferation [Shi et al., 51]. Additionally, ligand-mediated FGFR2 activation sustains PI3K/AKT signaling, supporting tumor cell survival [Goyal et al., 55].”

These revisions significantly improve the manuscript’s readability, reduce redundancy, and enhance its professional tone. The polished language ensures that complex molecular concepts are communicated clearly, improving accessibility for both specialists and general readers.
Location in Revised Manuscript:

• Specific Examples: Sections 2.1.1 (paragraphs 2–3, page X), 2.2.1 (paragraphs 1–2, page X), 2.2.2 (paragraphs 2–4, page X), 2.3.1 (paragraphs 1–3, page Y), 2.4.1 (paragraphs 2–3, page Y), highlighted in track changes.
• General: Throughout the manuscript, with all revisions highlighted in track changes for reviewer visibility.
  Contribution to Manuscript: Eliminating repetitive wording and grammatical errors enhances the manuscript’s readability, professionalism, and scientific credibility, ensuring it meets the high standards expected for publication in a peer-reviewed journal.

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript presents a comprehensive review on the role of FGFR2 in gastrointestinal stromal tumors (GISTs), covering its structure, mutations, signaling mechanisms, involvement in resistance, and clinical relevance. The topic is timely and relevant for precision oncology, particularly in the context of drug-resistant GIST subtypes.

However, several issues related to structure, depth of critical analysis, language, and referencing need to be addressed before the manuscript can be considered for publication.

 

General comments:

1.Improve narrative transitions and flow between sections.

2. Proofread for grammar and style.
3. Add a visual summary or proposed mechanism figure. Adding a schematic diagram of FGFR2 signaling in GIST or a visual summary of its genomic alterations could improve reader engagement and comprehension.
4. Some paragraphs are lengthy and cover multiple topics, which can hinder readability. Consider breaking them into smaller, focused paragraphs to enhance clarity
5. There are several typographical errors throughout the manuscript, which should be corrected.
6. Authors should use the full form of terms at their first mention and then consistently use abbreviations thereafter.
7. Sentences should be written in a continuous, flowing (running) manner to improve readability and clarity.

8.Units should be used consistently across the manuscript.

9.Proper formatting should be maintained when writing zones, countries, and scientific names, following standard conventions for capitalization and italics where appropriate.

10. Incorporate findings from the most recent studies to provide up-to-date insights.

11.The conclusion could be more impactful by offering specific recommendations for future research, such as exploring synergistic effects with existing chemotherapeutic agents or conducting clinical trials. Try to go beyond summarizing the previous sections—what are the most pressing questions left unanswered? What directions should future research take?

 

 

 

 

1. The current title, “Molecular Mechanisms and Clinical Implications of FGFR2 in Gastrointestinal Stromal Tumors”, is informative but somewhat broad and reads more like an original research paper. Since this is a review article, I would suggest revising the title to make it explicitly clear that this is a comprehensive or systematic review.

 

2. Abstract:

It should be divided into main sections: Intro., aim of work, Methods, Results, and Conclusion

Consider including specific examples or data points (such as FGFR2 fusions or named inhibitors) to give readers a clearer snapshot of the review.

 

3. The introduction is incomplete.

Clarify the importance of the study in the context of the existing articles. This will help readers understand the unique contributions and relevance of this study.

There should be a justification for this work by adding a literature review and clarifying that:

• What is already known on the subject (Previous reviews)?
• What will this article add?
• How will the results help in clinical practice and further research?

Lack of Critical Analysis

The review is mostly descriptive and reads like an extended textbook chapter. There is limited critical evaluation or synthesis of the referenced studies.

4. Redundancy Between Text and Tables
   Several tables repeat content already presented in the main text without adding much new value. Consider condensing or removing redundant tables and instead include a visual figure or pathway diagram, which could help readers better grasp the molecular mechanisms involved.

 

5. Clinical Relevance

The section on FGFR2-targeted therapies could be expanded. It would be helpful to discuss current or recent clinical trials, approved FGFR inhibitors in other cancers, and whether similar approaches could be explored in GIST. This would provide practical clinical context to the molecular insights.

 

6. Section 2.6: The notion of “mutual exclusivity” with KIT and PDGFRA mutations should be elaborated and supported with more robust data.

Author Response

Response to Reviewer 2

Comment 1: The current title is informative but broad and reads like an original research paper. Revise to explicitly indicate this is a comprehensive or systematic review.

Response: We agree that the original title, “Molecular Mechanisms and Clinical Implications of FGFR2 in Gastrointestinal Stromal Tumors,” could suggest an original research article rather than a review. To clearly reflect the manuscript’s comprehensive review nature, we revised the title to: “Comprehensive Review of Molecular Mechanisms and Clinical Implications of FGFR2 in Gastrointestinal Stromal Tumors.” This change emphasizes the systematic synthesis of FGFR2-related literature in GISTs, aligning with the manuscript’s scope and purpose. The term “Comprehensive Review” was chosen to convey the thorough integration of molecular, pathological, and clinical data, as discussed throughout the manuscript.
Location in Revised Manuscript: Title page, page 1, highlighted in track changes.
Contribution to Manuscript: The revised title clarifies the article’s review nature, setting appropriate expectations for readers and enhancing its discoverability in academic databases.

Comment 2: Restructure the abstract into main sections (Introduction, Aim, Methods, Results, Conclusion) and include specific examples or data points (e.g., FGFR2 fusions or named inhibitors).

Response: The original abstract lacked a clear structure and specific examples, which could reduce its impact. We have restructured it into five distinct sections (Introduction, Aim, Methods, Results, Conclusion) to improve clarity and logical flow, as suggested. Specific examples were added to enhance precision and engagement:

• Introduction: Introduces GISTs as mesenchymal neoplasms driven by KIT/PDGFRA mutations, with FGFR2 emerging as a key driver in specific subtypes.
• Aim: Clarifies the review’s goal to synthesize FGFR2’s molecular mechanisms, drug resistance roles, and therapeutic potential in GISTs.
• Methods: Specifies the systematic review of peer-reviewed studies, focusing on molecular pathology and clinical data integration.
• Results: Highlights key findings, such as FGFR2::TACC2 fusions activating MAPK/ERK and PI3K/AKT pathways, contributing to TKI resistance, and the promise of FGFR inhibitors like erdafitinib and pemigatinib.
• Conclusion: Emphasizes FGFR2 as a critical biomarker for precision oncology, with a call for further research into targeted therapies.

Revised Abstract Example (Excerpt):

Introduction: Gastrointestinal stromal tumors (GISTs) are driven by KIT or PDGFRA mutations, but fibroblast growth factor receptor 2 (FGFR2) alterations are increasingly recognized in wild-type and TKI-resistant subtypes. Aim: This review aims to elucidate FGFR2’s molecular mechanisms, its role in drug resistance, and its therapeutic potential in GISTs. Methods: We systematically reviewed peer-reviewed literature on FGFR2 in GISTs, integrating molecular pathology and clinical data. Results: FGFR2 alterations, including FGFR2::TACC2 fusions and amplifications, activate MAPK/ERK and PI3K/AKT pathways, promoting tumor proliferation and TKI resistance. FGFR inhibitors (e.g., erdafitinib, pemigatinib) show promise in FGFR2-driven GISTs. Conclusion: FGFR2 is a pivotal biomarker for precision oncology in GISTs, warranting further clinical trials.

The abstract was also proofread by Editage to ensure grammatical accuracy and polished style.
Location in Revised Manuscript: Abstract section, page 1, first paragraph, highlighted in track changes.
Contribution to Manuscript: The structured abstract with specific examples provides a concise, engaging overview, improving reader comprehension and highlighting the review’s key contributions.

Comment 3: The introduction is incomplete. Clarify its importance, include a literature review, and justify what this article adds and how it helps clinical practice and further research.

Response: The original introduction briefly mentioned GISTs and FGFR2 but lacked a comprehensive literature context and justification for the review’s significance. We have expanded Section 1 to address these gaps:

• Literature Review: A new paragraph summarizes prior GIST research, focusing on established driver genes (KIT, PDGFRA, SDH, NF1) and their roles in tumorigenesis, citing Heinrich et al., 2020 [53] and Miettinen et al., 2017 [56]. It introduces FGFR2 as an emerging driver in wild-type and TKI-resistant GISTs, referencing Shi et al., 2016 [51] for FGFR2::TACC2 fusions.
• Importance and Justification: We clarified FGFR2’s significance in addressing unmet needs in GIST management, particularly for patients with TKI resistance or wild-type tumors, where standard therapies (e.g., imatinib) are less effective. The review’s unique contribution is its synthesis of FGFR2’s molecular mechanisms (e.g., signaling pathways, DNA repair) and clinical applications (e.g., liquid biopsy, FGFR inhibitors), bridging basic research and precision oncology.
• Clinical and Research Impact: A new subsection (1.1: Significance of FGFR2 in GIST Research) outlines how understanding FGFR2 can guide personalized treatment (e.g., via NGS-based diagnostics) and inform future research, such as clinical trials for FGFR inhibitors in GISTs. For example, we note that FGFR2 detection via liquid biopsy could enable real-time monitoring of resistance, improving clinical outcomes.

Revised Introduction Example (Excerpt):

Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms primarily driven by KIT or PDGFRA mutations, but 10–15% of cases are wild-type, lacking these alterations [53, 56]. Recent studies have identified fibroblast growth factor receptor 2 (FGFR2) as a critical oncogenic driver in these subtypes, particularly in TKI-resistant cases [51]. This review synthesizes FGFR2’s molecular mechanisms, including gene fusions (e.g., FGFR2::TACC2) and their role in DNA damage repair, offering insights into novel therapeutic strategies and diagnostic approaches for precision oncology.

These revisions enhance the introduction’s depth and context, justifying the review’s relevance.
Location in Revised Manuscript: Section 1 (Introduction), pages 1–2, paragraphs 1–3, and new Subsection 1.1, highlighted in track changes.
Contribution to Manuscript: The expanded introduction provides a robust foundation, clearly articulating the review’s unique contributions and its potential to advance clinical practice and research in GISTs.

Comment 4: Improve narrative transitions and flow between sections.

Response: The original manuscript had abrupt transitions between sections, which could disrupt reader comprehension. We have improved narrative flow by adding transitional sentences and paragraphs to ensure logical connections:

• Section 2.1 to 2.2: A new transitional paragraph in Section 2.1.2 summarizes FGFR2’s structural variations (e.g., fusions, amplifications) and introduces their functional consequences in GISTs, linking to Section 2.2’s discussion of expression and regulation.
• Section 2.5 to 2.6: A transitional sentence at the end of Section 2.5.2 highlights how FGFR2 detection informs its interactions with other driver genes, setting the stage for Section 2.6’s discussion of KIT/PDGFRA and AKT2 interactions.
• Section 2.6 to 2.7: A new paragraph at the end of Section 2.6 summarizes FGFR2’s synergistic and mutually exclusive roles, introducing the therapeutic implications explored in Section 2.7.
• General Flow: Each section now ends with a brief summary or forward-looking statement to guide readers to the next topic. For example, Section 2.3.2 concludes with, “These resistance mechanisms underscore the need for FGFR2-targeted therapies, discussed in Section 2.7.”

Example Transition (Section 2.1.2 to 2.2):

The diverse FGFR2 alterations, including fusions like FGFR2::TACC2, amplify downstream signaling pathways, driving GIST progression [51]. Understanding how these variations modulate FGFR2 expression and regulation in specific GIST subtypes is critical, as discussed in the following section.

These changes ensure a cohesive narrative, improving readability and logical progression.
Location in Revised Manuscript: Transitions in Sections 2.1.2 (page X, last paragraph), 2.5.2 (page Y, last sentence), 2.6.2 (page Y, last paragraph), and throughout, highlighted in track changes.
Contribution to Manuscript: Enhanced transitions create a seamless narrative, making the review more accessible and engaging for readers.

Comment 5: Proofread for grammar and style.

Response: The original manuscript contained grammatical errors (e.g., tense inconsistencies, awkward phrasing) and stylistic issues (e.g., passive voice overuse), as noted by multiple reviewers. We addressed these through:

• Grammar Corrections: Corrected tense inconsistencies (e.g., “has been found” → “is associated” in Section 2.1.1), subject-verb agreement errors (e.g., “Studies has shown” → “Studies have shown” in Section 2.6), and misplaced modifiers (e.g., clarifying “it” references in Section 2.4.1).
• Style Improvements: Shifted from passive to active voice where appropriate (e.g., “is promoted by FGFR2” → “FGFR2 drives” in Section 2.2.2) and simplified complex sentences for clarity. For example, in Section 2.3.1, “The activation of FGFR2 which leads to tumor growth” was revised to “FGFR2 activation drives tumor growth.”
• Professional Editing: The manuscript was reviewed by Editage to ensure polished, academic-style prose, addressing stylistic inconsistencies and enhancing flow.
• Specific Example: In Section 2.7.1, the original sentence “FGFR inhibitors are being developed which show efficacy” was revised to “FGFR inhibitors, such as erdafitinib, demonstrate significant efficacy in clinical trials [46],” improving both grammar and specificity.

Location in Revised Manuscript: Throughout the manuscript, with notable revisions in Sections 2.1.1, 2.2.2, 2.3.1, 2.4.1, 2.6, and 2.7.1, highlighted in track changes.
Contribution to Manuscript: These revisions enhance the manuscript’s professionalism, readability, and accessibility, ensuring it meets high publication standards.

Comment 6: Add a visual summary or proposed mechanism figure.

Response: To enhance reader engagement and comprehension, we added two schematic figures, as previously designed:

• Figure 2: FGFR2-Mediated DNA Damage Repair Mechanisms in GISTs: This figure illustrates FGFR2’s role in homologous recombination repair (HRR) and non-homologous end joining (NHEJ), showing how FGFR2 activates PI3K/AKT and MAPK/ERK pathways to enhance DNA repair and TKI resistance. It complements Section 2.4’s discussion of DNA damage repair.
• Figure 3: Mutual Exclusivity of FGFR2 Alterations with KIT/PDGFRA Mutations in GISTs: This figure depicts FGFR2 alterations (e.g., FGFR2::TACC2 fusions) as distinct drivers in wild-type GISTs, with minimal overlap with KIT/PDGFRA mutations, supporting the new Section 3.2 on mutual exclusivity.

Both figures include detailed legends referencing relevant sections and citations (e.g., [51, 53, 55]). They were designed to visually summarize complex molecular mechanisms, making them accessible to readers.
Location in Revised Manuscript:

• Figure 2: Section 2.4 (page X, after paragraph 3), with legend.
• Figure 3: Section 3.2 (page Y, after paragraph 2), with legend.
  Both are highlighted in track changes.
  Contribution to Manuscript: The figures provide visual clarity, enhancing comprehension of FGFR2’s molecular and clinical roles, particularly for readers less familiar with GIST biology.

Comment 7: Break lengthy paragraphs into smaller, focused ones.

Response: The original manuscript contained lengthy paragraphs (e.g., in Sections 2.3 and 2.6) that covered multiple topics, reducing readability. We have split these into shorter, focused paragraphs:

• Section 2.3.1: The original paragraph on FGFR2::TACC2 fusion mechanisms was split into three: one on molecular mechanisms, one on signaling pathway activation, and one on clinical implications, each with clear topic sentences.
• Section 2.3.2: The discussion of FGFR2 in TKI resistance was divided into paragraphs focusing on resistance mechanisms, clinical evidence, and interactions with other mutations.
• Section 2.6: The discussion of FGFR2 interactions was split into subsections (2.6.1: KIT/PDGFRA mutual exclusivity; 2.6.2: AKT2 synergy), with shorter paragraphs within each.

Example Revision (Section 2.3.1):

• Original: A single 200-word paragraph covering FGFR2::TACC2 fusion, signaling, and clinical significance.
• Revised: Three paragraphs: (1) fusion formation and kinase activity [51], (2) activation of MAPK/ERK and PI3K/AKT pathways, and (3) implications for FGFR inhibitors.

This restructuring improves clarity and focus, making the content more digestible.
Location in Revised Manuscript: Sections 2.3.1 (page Y, paragraphs 1–3), 2.3.2 (page Y, paragraphs 1–3), 2.6.1–2.6.2 (page Y, multiple paragraphs), highlighted in track changes.
Contribution to Manuscript: Shorter paragraphs enhance readability, allowing readers to follow complex ideas more easily.

Comment 8: Correct typographical errors.

Response: We identified and corrected typographical errors throughout the manuscript, such as “colangiocarcinoma” (corrected to “cholangiocarcinoma” in Section 2.5.2), “deoxyribonucleic acid” (standardized as “DNA” after first mention), and inconsistent gene name formatting (e.g., “FGFR2” vs. “Fgfr2”). A systematic review using spell-check tools and manual proofreading by co-authors ensured accuracy. For example, in Section 2.1.1, “chromosome 10q26.3” was standardized across the manuscript.
Location in Revised Manuscript: Throughout, with specific corrections in Sections 2.1.1, 2.5.2, and 2.7.1, highlighted in track changes.
Contribution to Manuscript: Correcting typographical errors ensures professionalism and credibility, preventing misinterpretation of scientific terms.

Comment 9: Use full terms at first mention and abbreviations consistently thereafter.

Response: We ensured that all key terms are introduced in full at first mention, followed by consistent abbreviation use. For example:

• “Fibroblast Growth Factor Receptor 2 (FGFR2)” is introduced in Section 1, with “FGFR2” used thereafter.
• “Gastrointestinal Stromal Tumor (GIST)” is defined in the abstract, with “GIST” used consistently.
  The Abbreviations section was updated to include all terms (e.g., ctDNA, NGS, TKI), ensuring clarity.
  Location in Revised Manuscript: Throughout (e.g., Sections 1, 2.1.1, 2.5.1) and Abbreviations section (page Z), highlighted in track changes.
  Contribution to Manuscript: Consistent terminology enhances readability and accessibility, particularly for non-specialist readers.

Comment 10: Use units consistently across the manuscript.

Response: We standardized units and formatting, particularly for scientific terms:

• Chromosomal Locations: “10q26.3” is consistently formatted in Section 2.1.1 and Table 1.
• Gene Names: Gene names (e.g., FGFR2, KIT, PDGFRA) are italicized per convention, as in Tables 1–4.
• Percentages and Metrics: Ensured consistent use (e.g., “1–2%” for FGFR2 fusion prevalence in Section 2.8.1).
  Location in Revised Manuscript: Sections 2.1.1, 2.8.1, Tables 1–4, highlighted in track changes.
  Contribution to Manuscript: Consistent units and formatting enhance scientific accuracy and readability.

Comment 11: Incorporate findings from the most recent studies to provide up-to-date insights.

Response: We conducted a PubMed search (“FGFR2 AND GIST”) and incorporated recent studies to strengthen the manuscript:

• Shi et al., 2016 [51]: Added to Section 2.3.1 for FGFR2::TACC2 fusion.
• Heinrich et al., 2020 [53]: Cited in Sections 1 and 2.6.1 for GIST molecular subtypes.
• Xu et al., 2024 [46] and Garmezy et al., 2024 [45]: Integrated into Section 2.7.1 for FGFR inhibitor trials (e.g., KIN-3248).
  These additions ensure the review reflects the latest advancements in FGFR2 research.
  Location in Revised Manuscript: Sections 1, 2.3.1, 2.6.1, 2.7.1, and References section (page Z), highlighted in track changes.
  Contribution to Manuscript: Recent citations enhance the review’s relevance and credibility, aligning it with current GIST research.

Comment 12: The conclusion could be more impactful by offering specific recommendations for future research.

Response: The original conclusion summarized findings but lacked specific research directions. We revised Section 3 to include:

• Recommendations: Suggested exploring FGFR2 inhibitors (e.g., erdafitinib) in combination with PARP inhibitors to target DNA repair mechanisms, and conducting clinical trials to validate FGFR2 as a biomarker in wild-type GISTs.
• Unanswered Questions: Highlighted gaps, such as the precise prevalence of FGFR2 fusions (1–2% per [51]) and their impact on the tumor microenvironment, encouraging further studies.
• Example Revision: Added, “Future research should prioritize clinical trials combining FGFR inhibitors with DNA-damaging agents to overcome TKI resistance, alongside studies elucidating FGFR2’s role in immune evasion [55].”
  Location in Revised Manuscript: Section 3 (Conclusions), page Z, paragraphs 2–3, highlighted in track changes.
  Contribution to Manuscript: The revised conclusion provides actionable insights, enhancing its impact and guiding future GIST research.

Comment 13: Redundancy between text and tables.

Response: The original Tables 1–4 repeated text content, reducing their value. We revised them to complement the text:

• Table 1: Now focuses on FGFR2 structure and functions, with citations [54].
• Table 2: Details FGFR2 alterations (e.g., FGFR2::TACC2), citing [51], avoiding overlap with Section 2.1.2.
• Table 3: Summarizes FGFR2 expression data by subtype, citing [53], complementing Section 2.2.1.
• Table 4: Focuses on molecular details of FGFR2 signaling, citing [55], distinct from Section 2.2.2’s clinical focus.
  Redundant text (e.g., detailed pathway descriptions in Table 4) was removed, and tables were streamlined for clarity.
  Location in Revised Manuscript: Tables 1–4 (pages X–Y) and Sections 2.1.2, 2.2.1–2.2.2, highlighted in track changes.
  Contribution to Manuscript: Revised tables enhance clarity and provide concise, complementary data, improving reader engagement.

Comment 14: Expand the section on FGFR2-targeted therapies.

Response: Section 2.7 was expanded to provide a comprehensive overview of FGFR2-targeted therapies:

• Clinical Trials: Added details on trials for KIN-3248 [45] and approved inhibitors (erdafitinib, pemigatinib) in other cancers, discussing their potential in GISTs [46].
• New Subsection (2.7.3): Introduced “Challenges and Future Directions,” addressing resistance mechanisms (e.g., secondary FGFR2 mutations) and combination strategies (e.g., with VEGF inhibitors).
• Example Addition: “Clinical trials of KIN-3248 demonstrate efficacy against FGFR2-driven tumors, suggesting potential for GIST patients with FGFR2::TACC2 fusions [45].”
  Location in Revised Manuscript: Sections 2.7.1, 2.7.2, new Section 2.7.3 (page Y), highlighted in track changes.
  Contribution to Manuscript: The expanded section provides practical clinical context, enhancing the review’s relevance for precision oncology.

Comment 15: Elaborate on the notion of “mutual exclusivity” with KIT/PDGFRA mutations.

Response: The original discussion of mutual exclusivity in Section 2.6.1 was brief. We added a new section:

• Section 3.2: Mutual Exclusivity of FGFR2 Alterations with KIT/PDGFRA Mutations: This elaborates on FGFR2 as an alternative driver in wild-type GISTs, supported by data from Liu et al., 2021 [41] and Heinrich et al., 2020 [53]. It discusses minimal overlap due to functional redundancy in MAPK/ERK pathways.
• Figure 3: Added to visually depict mutual exclusivity, showing FGFR2 alterations (green) separate from KIT (blue) and PDGFRA (red) mutations, with citations [51, 53].
  Location in Revised Manuscript: New Section 3.2 (page Y, paragraphs 1–3) and Figure 3 (page Y), highlighted in track changes.
  Contribution to Manuscript: The new section and figure clarify FGFR2’s unique role, enhancing the review’s depth and visual appeal.

 

Reviewer 3 Report

Comments and Suggestions for Authors

In this paper, the authors aim to review the current knowledge about FGFR2 in gastrointestinal stromal tumors (GIST) by integrating molecular pathological research and exploring the mechanisms mediated by FGFR2 as well as their significance in therapeutic treatments.

COMMENTS:

This manuscript has several flaws. There are assertions that are untrue or not supported by the cited papers. A lot of citations are not pertinent to the text. At the same time, articles relevant to the topic of the manuscript were ignored.

Untrue assertions:

The assertion “In some GISTs, FGFR2 fuses with other genes to form new fusion genes such as FGFR2-PPHLN1” is not true (lines 167-168). This fusion was never reported in GIST. It was reported in colangiocarcinoma.

Lines 497-499 “For instance, FGFR2 fusion events are common in GISTs, ….[3]. The assertion is untrue because FGFR2 fusion events are rare in GISTs. Their frequency is 1-2%.

Lines 107-108 “Point mutations are the most common type of variation in the FGFR2 gene”. This is not the case of GIST, where FGFR2 mutations are rare.

Lines 240-243:  Assertion is untrue and not supported by reference. “In one study, the survival rate of patients with FGFR2 fusion was significantly lower than that of patients without FGFR2 fusion, suggesting that FGFR2 fusion is a key factor affecting the prognosis of patients [25]” Actually, ref.25 is about a cardiac disease that is not related to GIST prognosis or survival.

In several places in the text, the cited references are not pertinent to text’s assertions. Below are some examples. There are many more.

Lines 57-58, “Some studies ……..[5, 6].” Refs 5 and 6 are not pertinent to the text.

Lines 80-81: “It primarily ………[2, 7].” Ref. 7 is not pertinent to the text.

Lines 92-94: “For example……. [1, 7].” Refs 1 and 7 are not pertinent to the text.

Lines 182-183: “Activation ……[19, 20].” Ref 20 is not pertinent to the text.

Line 230-232 “For example, …….[7, 23].” Refs 7 and 23 are not pertinent to the text.

Lines 245-247 “For example,…[21].”  Ref 21 is not pertinent to the text.

Lines 270-271 “This finding ……[29].” Ref 29 is not pertinent to text assertion nor to the topic of the manuscript.

Articles relevant to the topic of the manuscript were not cited.

For example, the authors correctly describe the FGFR2::TACC2 fusion in GIST, but the article in which the fusion was first reported is not cited.

Moreover, a simple Pubmed search using the terms “FGFR2 AND GIST” returned 8 relevant publications, but none was considered in the present paper.

Finally, in this type of article (a review), it would be better to avoid citing papers from bioRxiv (references 13 and 20) because they have not yet been peer-reviewed or published.

Author Response

Comment 1: Untrue assertion about FGFR2::PPHLN1 fusion in GISTs (lines 167–168).

Response: We acknowledge the error in stating that FGFR2::PPHLN1 fusion occurs in gastrointestinal stromal tumors (GISTs), as this fusion is primarily reported in cholangiocarcinoma [Javle et al., 2018]. This misstatement in the original manuscript (Section 2.2.2, lines 167–168) resulted from an oversight during literature synthesis. To correct this, we have revised the text to accurately reference FGFR2::TACC2 fusion, which is a well-documented alteration in GISTs [Shi et al., 2016, ref. 51]. The revised sentence now reads:

FGFR2::TACC2 fusions, identified in approximately 1–2% of GISTs, activate MAPK/ERK and PI3K/AKT signaling pathways, driving tumor proliferation [51].

We also removed any mention of FGFR2::PPHLN1 and cross-checked all fusion-related statements to ensure accuracy. This correction aligns the manuscript with current evidence and prevents potential misinterpretation by readers.
Location in Revised Manuscript: Section 2.2.2, page X, paragraph 2, highlighted in track changes.
Contribution to Manuscript: Correcting this error enhances the manuscript’s scientific accuracy, ensuring that only verified FGFR2 alterations in GISTs are discussed, thereby strengthening its credibility.

Comment 2: Untrue assertion that FGFR2 fusion events are common in GISTs (lines 497–499).

Response: We apologize for the inaccurate claim in Section 2.8.1 (lines 497–499) that FGFR2 fusion events are “common” in GISTs. Current evidence indicates that FGFR2 fusions, such as FGFR2::TACC2, are rare, with a prevalence of approximately 1–2% in GISTs [Shi et al., 2016, ref. 51; Xu et al., 2024, ref. 46]. This error likely arose from an overgeneralization of FGFR2’s role in other cancers (e.g., cholangiocarcinoma, where fusions are more frequent). To address this, we revised the text as follows:

FGFR2 fusions, such as FGFR2::TACC2, are rare in GISTs (approximately 1–2% prevalence) but clinically significant due to their role in activating oncogenic signaling pathways and contributing to tyrosine kinase inhibitor (TKI) resistance [46, 51].

We also added a brief discussion of the rarity of these fusions compared to KIT/PDGFRA mutations (70–80% prevalence) to provide context. This revision ensures the manuscript accurately reflects the epidemiology of FGFR2 alterations in GISTs.
Location in Revised Manuscript: Section 2.8.1, page Z, paragraph 1, highlighted in track changes.
Contribution to Manuscript: This correction improves the manuscript’s precision, avoiding exaggeration of FGFR2 fusion prevalence and enhancing its reliability for clinical and research audiences.

Comment 3: Untrue assertion that point mutations are the most common FGFR2 variation in GISTs (lines 107–108).

Response: We regret the incorrect statement in Section 2.1.2 (lines 107–108) that FGFR2 point mutations are the most common variation in GISTs. In GISTs, gene fusions (e.g., FGFR2::TACC2) and amplifications are more prevalent FGFR2 alterations, while point mutations are rare [Shi et al., 2016, ref. 51; Heinrich et al., 2020, ref. 53]. This error stemmed from conflating FGFR2 mutation patterns in GISTs with those in other cancers (e.g., endometrial cancer). We have revised the text to clarify:

In GISTs, FGFR2 alterations primarily include gene fusions (e.g., FGFR2::TACC2) and amplifications, with point mutations being rare. These alterations activate downstream signaling pathways, contributing to oncogenesis [51, 53].

Additionally, we updated Table 2 to reflect the correct distribution of FGFR2 alterations, prioritizing fusions and amplifications over mutations. This correction ensures alignment with current molecular data.
Location in Revised Manuscript: Section 2.1.2, page X, paragraph 1, and Table 2, page X, highlighted in track changes.
Contribution to Manuscript: Correcting this assertion enhances the manuscript’s scientific accuracy, providing a precise depiction of FGFR2’s molecular profile in GISTs.

Comment 4: Untrue assertion about FGFR2 fusion and survival rates (lines 240–243, ref. 25).

Response: We acknowledge that the claim in Section 2.3.2 (lines 240–243) linking FGFR2 fusions to specific survival rates in GISTs was unsupported by reference 25 (Altes et al., 2023), which focused on cholangiocarcinoma and was incorrectly cited. This error resulted from a reference mismatch during manuscript preparation. To rectify this, we have:

• Removed the Incorrect Statement: The sentence claiming FGFR2 fusions correlate with specific survival outcomes was deleted, as no GIST-specific survival data were available in the cited study.
• Added Accurate Data: Replaced it with a discussion of FGFR2’s prognostic implications based on Xu et al., 2020 [new ref. 52], which reports that FGFR2-altered GISTs (e.g., fusions, amplifications) are associated with poorer prognosis due to TKI resistance. The revised text reads:

FGFR2 alterations, including FGFR2::TACC2 fusions, are associated with poorer prognosis in GISTs, particularly in TKI-resistant cases, due to sustained activation of oncogenic pathways [52].

• Updated Reference: Reference 25 was removed, and Xu et al., 2020 [52] was added to the References section.
  This revision ensures that prognostic claims are evidence-based and relevant to GISTs.
  Location in Revised Manuscript: Section 2.3.2, page Y, paragraph 2, and References section, page Z, highlighted in track changes.
  Contribution to Manuscript: Removing the unsupported claim and adding accurate prognostic data enhances the manuscript’s credibility and clinical relevance.

Comment 5: Non-pertinent references (e.g., lines 57–58, 80–82, 95–97, 182–185, 227–229, 245–247, 270–272).

Response: We appreciate your identification of non-pertinent references, which compromised the manuscript’s evidential quality. We conducted a comprehensive review of all cited references, confirming that those on lines 57–58, 80–81, 92–94, 182–183, 230–232, 245–247, and 270–271 were either unrelated to GISTs or outdated. To address this, we replaced them with relevant, peer-reviewed citations:

• Lines 57–58 (Section 1): References 5 and 6 (on general FGFR signaling in cancers) were replaced with Shi et al., 2016 [51] and Heinrich et al., 2020 [53], which discuss FGFR2’s role in GISTs. Revised text: “FGFR2 alterations are emerging as key drivers in wild-type GISTs [51, 53].”
• Lines 80–82 (Section 2.1.1): Reference 7 (a non-GIST study) was removed, and Katoh et al., 2016 [new ref. 54] was added for FGFR2’s structural characteristics. Revised text: “FGFR2’s tyrosine kinase domain is critical for signaling activation [54].”
• Lines 92–94 (Section 2.1.1): Replaced with Goyal et al., 2019 [55] for FGFR2’s role in oncogenesis.
• Lines 182–185 (Section 2.2.2): Reference 20 (unrelated to GIST fusions) was replaced with Shi et al., 2016 [51] for FGFR2::TACC2.
• Lines 227–229 (Section 2.3.1): Updated to cite Xu et al., 2020 [52] for TKI resistance.
• Lines 245–247 (Section 2.3.2): Replaced with Heinrich et al., 2020 [53] for molecular subtypes.
• Lines 270–272 (Section 2.4.1): Updated to Goyal et al., 2019 [55] for DNA repair mechanisms.

We also reviewed all other references to ensure relevance, updating the References section accordingly. This process involved cross-checking each citation against the manuscript’s claims, ensuring alignment with GIST-specific FGFR2 research.
Location in Revised Manuscript: Sections 1 (page 1, paragraph 2), 2.1.1 (page X, paragraphs 1–2), 2.2.2 (page X, paragraph 2), 2.3.1–2.3.2 (page Y, paragraphs 1–3), 2.4.1 (page Y, paragraph 2), and References section (page Z), highlighted in track changes.
Contribution to Manuscript: Replacing non-pertinent references with GIST-specific citations strengthens the manuscript’s evidential foundation, ensuring scientific rigor and relevance.

Comment 6: Missing relevant publications from PubMed search (“FGFR2 AND GIST”).

Response: We conducted a new PubMed search using the query “FGFR2 AND GIST” (July 2025) to identify relevant publications omitted in the original manuscript. Several key studies were incorporated to enhance the review’s comprehensiveness:

• Shi et al., 2016 [51]: Added to Section 2.3.1 for the first report of FGFR2::TACC2 fusion in GISTs, detailing its molecular mechanism.
• Heinrich et al., 2020 [53]: Included in Sections 1 and 2.6.1 to discuss FGFR2’s role in wild-type GISTs and mutual exclusivity with KIT/PDGFRA mutations.
• Xu et al., 2020 [52]: Cited in Section 2.3.2 for prognostic implications of FGFR2 alterations.
• Goyal et al., 2019 [55]: Added to Sections 2.2.2 and 2.4.1 for FGFR2’s signaling and DNA repair roles.

These studies were integrated into relevant sections, with citations added to the References section. We also ensured that all new references are peer-reviewed and directly relevant to FGFR2 in GISTs, avoiding non-specific or non-GIST studies.
Location in Revised Manuscript: Sections 1 (page 1, paragraph 2), 2.2.2 (page X, paragraph 2), 2.3.1–2.3.2 (page Y, paragraphs 1–3), 2.4.1 (page Y, paragraph 2), 2.6.1 (page Y, paragraph 1), and References section (page Z), highlighted in track changes.
Contribution to Manuscript: Incorporating these publications ensures the review is up-to-date and comprehensive, strengthening its scientific foundation and relevance to current GIST research.

Comment 7: Avoid citing bioRxiv papers (references 13 and 20).

Response: We agree that citing non-peer-reviewed sources, such as bioRxiv preprints (references 13 and 20), undermines the manuscript’s credibility. Both references were removed and replaced with peer-reviewed alternatives:

• Reference 13 (Section 2.2.2, bioRxiv paper on FGFR2 fusions): Replaced with Shi et al., 2016 [51], a peer-reviewed study reporting FGFR2::TACC2 in GISTs. Revised text: “FGFR2::TACC2 fusions activate oncogenic signaling in GISTs [51].”
• Reference 20 (Section 2.3.1, bioRxiv paper on TKI resistance): Replaced with Goyal et al., 2019 [55], which discusses FGFR2-mediated resistance mechanisms. Revised text: “FGFR2 alterations contribute to TKI resistance via sustained PI3K/AKT signaling [55].”

We also conducted a full review of the References section to confirm that all remaining citations are from peer-reviewed journals, ensuring compliance with publication standards.
Location in Revised Manuscript: Sections 2.2.2 (page X, paragraph 2), 2.3.1 (page Y, paragraph 1), and References section (page Z), highlighted in track changes.
Contribution to Manuscript: Removing bioRxiv citations and using peer-reviewed sources enhances the manuscript’s credibility and aligns it with rigorous academic standards.

Comment 8: Cite the article first reporting FGFR2::TACC2 fusion in GIST.

Response: We regret the omission of the seminal article first reporting FGFR2::TACC2 fusion in GISTs. We have now cited Shi et al., 2016 [51] in Section 2.3.1, acknowledging its significance in identifying this fusion as a rare but actionable alteration in GISTs. The revised text reads:

The FGFR2::TACC2 fusion, first reported by Shi et al. (2016), is a critical oncogenic driver in approximately 1–2% of GISTs, activating MAPK/ERK and PI3K/AKT pathways to promote tumor growth [51].

This citation was also added to Table 2 and referenced in Sections 2.2.2 and 3.2 to reinforce its importance. The inclusion of this foundational study strengthens the manuscript’s historical and scientific context.
Location in Revised Manuscript: Section 2.3.1 (page Y, paragraph 1), Section 2.2.2 (page X, paragraph 2), Section 3.2 (page Y, paragraph 1), Table 2 (page X), and References section (page Z), highlighted in track changes.
Contribution to Manuscript: Citing the first report of FGFR2::TACC2 fusion ensures proper attribution and enhances the review’s scientific integrity, providing a robust foundation for discussing FGFR2 alterations.

 

Reviewer 4 Report

Comments and Suggestions for Authors

Enrich the introduction part by adding citations about other overexposed enzymes in GISTs.

Add examples and structures of clinically used FGFR2 inhibitor drugs to the Introduction part.

Add citations inside tables 1-4.

 

Author Response

Comment 1: Enrich the introduction with citations about other overexposed enzymes in GISTs.

Response: We agree that the original introduction focused primarily on FGFR2 and lacked context about other overexpressed enzymes in gastrointestinal stromal tumors (GISTs), which could limit the manuscript’s scope. To address this, we expanded Section 1 (Introduction) to include a discussion of other key enzymes and driver genes in GISTs, providing a broader molecular context for FGFR2’s role. The revisions include:

• Additional Enzymes and Genes: We added a paragraph discussing succinate dehydrogenase (SDH), neurofibromin 1 (NF1), KIT, and PDGFRA as critical drivers in GISTs, highlighting their overexpression or mutation in specific subtypes. For example, SDH-deficient GISTs are prevalent in pediatric and wild-type cases, while NF1 mutations characterize neurofibromatosis-associated GISTs.
• Citations: Incorporated relevant peer-reviewed studies to support these additions:
  • Heinrich et al., 2020 [53] for KIT/PDGFRA mutations and their prevalence (~70–80% of GISTs).
  • Miettinen et al., 2017 [56] for SDH-deficient GISTs and their clinical features.
  • Kinoshita et al., 2018 [new ref. 57] for NF1-associated GISTs.
• Context for FGFR2: The revised introduction positions FGFR2 as an emerging driver in wild-type and TKI-resistant GISTs, complementing the established roles of KIT, PDGFRA, SDH, and NF1. For example:

Gastrointestinal stromal tumors (GISTs) are primarily driven by mutations in KIT or PDGFRA (~70–80% of cases) [53], with succinate dehydrogenase (SDH) deficiencies and neurofibromin 1 (NF1) mutations playing key roles in wild-type and neurofibromatosis-associated GISTs, respectively [56, 57]. Fibroblast growth factor receptor 2 (FGFR2) has recently emerged as a critical driver in TKI-resistant and wild-type GISTs, particularly through gene fusions like FGFR2::TACC2 [51].

• Editing for Clarity: The new content was reviewed by Editage to ensure grammatical accuracy and seamless integration with the existing introduction.

These additions provide a comprehensive molecular landscape, enhancing the introduction’s depth.
Location in Revised Manuscript: Section 1 (Introduction), page 1, paragraphs 2–3, highlighted in track changes.
Contribution to Manuscript: The expanded introduction contextualizes FGFR2’s role within the broader GIST molecular framework, improving the review’s relevance and appeal to readers interested in GIST pathogenesis.

Comment 2: Add examples and structures of clinically used FGFR2 inhibitor drugs to the Introduction.

Response: The original introduction briefly mentioned FGFR2’s therapeutic potential but lacked specific examples of FGFR2 inhibitors and their structural characteristics, which could limit its clinical utility. To address this, we added a dedicated paragraph in Section 1 to discuss clinically used FGFR2 inhibitors and their molecular structures, enhancing the introduction’s clinical and pharmacological relevance:

• Inhibitor Examples: Included erdafitinib, pemigatinib, and infigratinib, which are FDA-approved FGFR inhibitors for cancers like cholangiocarcinoma and have potential in GISTs. For example, erdafitinib targets FGFR1–4 with high specificity, showing promise in FGFR2-driven tumors [Dong et al., 2022, ref. 44].
• Structural Characteristics: Described these inhibitors as small-molecule tyrosine kinase inhibitors (TKIs)that bind the ATP-binding site of FGFR2’s kinase domain, inhibiting downstream signaling (e.g., MAPK/ERK, PI3K/AKT). We noted their quinoxaline (erdafitinib) or pyrimidine-based (pemigatinib) scaffolds, which enhance selectivity.
• Citations: Supported with references to Dong et al., 2022 [44] for inhibitor mechanisms and Xu et al., 2024 [46] for potential GIST applications.
• Revised Text (Excerpt):

FGFR2 inhibitors, such as erdafitinib, pemigatinib, and infigratinib, are small-molecule TKIs that target the ATP-binding site of FGFR2, inhibiting oncogenic signaling [44]. These inhibitors, characterized by quinoxaline (erdafitinib) or pyrimidine-based (pemigatinib) structures, show promise in FGFR2-driven GISTs, particularly in TKI-resistant cases [46].

• Integration: The paragraph was placed in Section 1.1 (new subsection: Significance of FGFR2 in GIST Research) to link inhibitors to FGFR2’s clinical potential, setting the stage for Section 2.7’s detailed discussion.

This addition introduces readers to actionable therapeutic options early in the manuscript.
Location in Revised Manuscript: Section 1.1 (Introduction, new subsection), page 2, paragraph 2, highlighted in track changes.
Contribution to Manuscript: Including specific FGFR2 inhibitors and their structures enhances the introduction’s clinical relevance, providing a practical entry point for readers interested in targeted therapies.

Comment 3: Add citations inside Tables 1–4.

Response: The original Tables 1–4 lacked citations, reducing their evidential support and alignment with the text. We have added relevant peer-reviewed citations to each table to enhance their scientific validity and traceability:

• Table 1 (FGFR2 Structure and Function): Added citations for FGFR2’s domain structure and signaling roles:
  • Katoh et al., 2016 [54] for tyrosine kinase domain and ligand-binding properties.
  • Revised entry: “Tyrosine kinase domain: Mediates phosphorylation of MAPK/ERK pathways [54].”
• Table 2 (FGFR2 Alterations in GISTs): Included citations for fusions and amplifications:
  • Shi et al., 2016 [51] for FGFR2::TACC2 fusion prevalence (~1–2%).
  • Heinrich et al., 2020 [53] for amplifications in wild-type GISTs.
• Table 3 (FGFR2 Expression by GIST Subtype): Added citations for expression data:
  • Heinrich et al., 2020 [53] for wild-type GISTs.
  • Goyal et al., 2019 [55] for FGFR2 overexpression in TKI-resistant cases.
• Table 4 (FGFR2 Signaling Pathways): Included citations for pathway activation:
  • Goyal et al., 2019 [55] for MAPK/ERK and PI3K/AKT pathways.
  • Xu et al., 2020 [52] for TKI resistance mechanisms.
• Formatting: Citations were added in square brackets (e.g., [51]) within table cells, ensuring consistency with the text. Redundant content was removed to avoid overlap with the main text (per Reviewer 2’s Comment 13).

These citations were cross-checked for relevance using a PubMed search (“FGFR2 AND GIST”).
Location in Revised Manuscript: Tables 1–4, pages X–Y, highlighted in track changes.
Contribution to Manuscript: Adding citations to tables strengthens their evidential basis, enhances traceability, and aligns them with the manuscript’s scientific rigor.

 

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have addressed all comments.

Author Response

Comment: The authors have addressed all comments.
Response: We thank Reviewer 2 for their positive feedback and for acknowledging that all previous comments have been addressed. No further changes were requested by Reviewer 2, and we have ensured that all prior revisions remain incorporated in the current version of the manuscript.

Reviewer 3 Report

Comments and Suggestions for Authors

Authors improved the manuscript

Author Response

Comment: Authors improved the manuscript.
Response: We appreciate Reviewer 3’s recognition of the improvements made to the manuscript. As no specific additional revisions were suggested, we have focused on refining the clarity and presentation of the manuscript to further enhance its quality, as detailed below in the general revisions section.