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Biomedicines
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Recent Advances of Receptor Tyrosine Kinases in Solid Tumors
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Recent Advances of Receptor Tyrosine Kinases in Solid Tumors

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (30 April 2025) | Viewed by 15916

Special Issue Editor

Dr. Parham Jabbarzadeh Kaboli

E-Mail Website
Guest Editor
Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan
Interests: molecular pharmacology; targeted-therapy; breast cancer; TNBC; receptor tyrosine kinase; tyrosine kinase inhibitors; akt signaling; c-MET

Special Issue Information

Dear Colleagues,

This Special Issue, "Recent Advances of Receptor Tyrosine Kinases in Solid Tumors", will mainly focus on the role of new therapies targeting Receptor Tyrosine Kinases and their downstream signaling in solid tumors.

Receptor tyrosine kinases (RTKs) are a large family of receptors with similar structures. RTKs are crucial targets for treating cancer. Since 2000, when the first tyrosine kinase inhibitor (TKI), imatinib, was approved to target multiple RTKs, three generations of TKIs have been developed. They have been involved in significant progress in the personalized treatment of cancer during the past twenty years. TKIs are approved for several solid tumors, especially against epidermal growth factor receptors (EGFR) in patients with non-small cell lung cancer (NSCLC) and against HER2 in metastatic and Her2-positive breast cancer. However, acquired resistance and the lack of response to TKIs are important challenges for the patients treated with these drugs. TKIs, combined with other targeted therapies, chemotherapy, or immunotherapy, have been recommended to address these issues. Furthermore, advanced therapeutic tools such as bispecific antibodies (e.g., against EGFR/c-MET for NSCLC; against PD-L1/c-MET for HCC) and antibody–drug conjugates (e.g., against ALK for neuroblastoma), as well as chimeric antigen receptor (CAR) T cell and CAR natural killer (NK) cell therapies targeting c-MET in gastric cancer and lung adenocarcinoma, have been recently developed in cancer research as perspective therapies for the RTK-targeted treatment of tumors.

I invite authors to submit original research and review articles focusing on the biological functions and therapeutic potential, highlighting the future direction of RTK signaling in solid tumors.

Dr. Parham Jabbarzadeh Kaboli
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • targeted-therapy
  • solid tumors
  • receptor tyrosine kinase
  • tyrosine kinase inhibitor
  • FDA
  • c-MET
  • VEGFR
  • EGFR
  • ALK
  • growth factor

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Published Papers (4 papers)

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Research

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11 pages, 1456 KiB  
Article
Differential Impact of Tumor Endothelial Angiopoietin-2 and Podoplanin in Lymphatic Endothelial Cells on HCC Outcomes with Tyrosine Kinase Inhibitor Treatment According to Sex
by Simone Lasagni, Rosina Maria Critelli, Fabiola Milosa, Dario Saltini, Filippo Schepis, Adriana Romanzi, Francesco Dituri, Grazia Serino, Lorenza Di Marco, Alessandra Pivetti, Filippo Scianò, Gianluigi Giannelli and Erica Villa
Biomedicines 2024, 12(7), 1424; https://doi.org/10.3390/biomedicines12071424 - 26 Jun 2024
Viewed by 1588
Abstract
Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. Curative treatments are available to a minority of patients, as HCC is often diagnosed at an advanced stage. For patients with unresectable and multifocal HCC, tyrosine kinase inhibitor drugs (TKIs) are [...] Read more.
Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. Curative treatments are available to a minority of patients, as HCC is often diagnosed at an advanced stage. For patients with unresectable and multifocal HCC, tyrosine kinase inhibitor drugs (TKIs) are the only potential treatment option. Despite extensive research, predictors of response to these therapies remain elusive. This study aimed to analyze the biological and histopathological characteristics of HCC patients treated with TKIs, focusing on angiogenesis and lymphangiogenesis. Immunohistochemistry quantified the expression of angiopoietin-2 (Ang2), lymphatic endothelial cells (LEC) podoplanin, and C-type Lectin Domain Family 2 (CLEC-2), key factors in neoangiogenesis and lymphangiogenesis. An increased expression of endothelial Ang2 and LEC podoplanin predicted a lower risk of metastasis. Female patients had significantly longer overall survival and survival on TKIs, associated with higher tumor expression of endothelial Ang2 and LEC podoplanin. Moreover, LEC podoplanin expression and a longer time on TKIs were independently correlated with improved survival on TKI therapy at Cox regression analysis. These findings suggest that endothelial Ang2 and LEC podoplanin could be potential biomarkers for predicting treatment outcomes and guiding therapeutic strategies in HCC patients treated with TKIs. Full article
(This article belongs to the Special Issue Recent Advances of Receptor Tyrosine Kinases in Solid Tumors)
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18 pages, 2379 KiB  
Article
Comparing the Efficacy of Two Generations of EGFR-TKIs: An Integrated Drug–Disease Mechanistic Model Approach in EGFR-Mutated Lung Adenocarcinoma
by Hippolyte Darré, Perrine Masson, Arnaud Nativel, Laura Villain, Diane Lefaudeux, Claire Couty, Bastien Martin, Evgueni Jacob, Michaël Duruisseaux, Jean-Louis Palgen, Claudio Monteiro and Adèle L’Hostis
Biomedicines 2024, 12(3), 704; https://doi.org/10.3390/biomedicines12030704 - 21 Mar 2024
Cited by 2 | Viewed by 2996
Abstract
Mutationsin epidermal growth factor receptor (EGFR) are found in approximately 48% of Asian and 19% of Western patients with lung adenocarcinoma (LUAD), leading to aggressive tumor growth. While tyrosine kinase inhibitors (TKIs) like gefitinib and osimertinib target this mutation, treatments often face challenges [...] Read more.
Mutationsin epidermal growth factor receptor (EGFR) are found in approximately 48% of Asian and 19% of Western patients with lung adenocarcinoma (LUAD), leading to aggressive tumor growth. While tyrosine kinase inhibitors (TKIs) like gefitinib and osimertinib target this mutation, treatments often face challenges such as metastasis and resistance. To address this, we developed physiologically based pharmacokinetic (PBPK) models for both drugs, simulating their distribution within the primary tumor and metastases following oral administration. These models, combined with a mechanistic knowledge-based disease model of EGFR-mutated LUAD, allow us to predict the tumor’s behavior under treatment considering the diversity within the tumor cells due to different mutations. The combined model reproduces the drugs’ distribution within the body, as well as the effects of both gefitinib and osimertinib on EGFR-activation-induced signaling pathways. In addition, the disease model encapsulates the heterogeneity within the tumor through the representation of various subclones. Each subclone is characterized by unique mutation profiles, allowing the model to accurately reproduce clinical outcomes, including patients’ progression, aligning with RECIST criteria guidelines (version 1.1). Datasets used for calibration came from NEJ002 and FLAURA clinical trials. The quality of the fit was ensured with rigorous visual predictive checks and statistical tests (comparison metrics computed from bootstrapped, weighted log-rank tests: 98.4% (NEJ002) and 99.9% (FLAURA) similarity). In addition, the model was able to predict outcomes from an independent retrospective study comparing gefitinib and osimertinib which had not been used within the model development phase. This output validation underscores mechanistic models’ potential in guiding future clinical trials by comparing treatment efficacies and identifying patients who would benefit most from specific TKIs. Our work is a step towards the design of a powerful tool enhancing personalized treatment in LUAD. It could support treatment strategy evaluations and potentially reduce trial sizes, promising more efficient and targeted therapeutic approaches. Following its consecutive prospective validations with the FLAURA2 and MARIPOSA trials (validation metrics computed from bootstrapped, weighted log-rank tests: 94.0% and 98.1%, respectively), the model could be used to generate a synthetic control arm. Full article
(This article belongs to the Special Issue Recent Advances of Receptor Tyrosine Kinases in Solid Tumors)
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14 pages, 3112 KiB  
Article
Clinical Significance and Expression Pattern of RIP5 and VGLL4 in Clear Cell Renal Cell Carcinoma Patients Treated with Sunitinib
by Tanja Tomić, Davor Tomić, Martina Vukoja, Marija Kraljević, Ivona Ljevak, Una Glamočlija, Vajdana Tomić, Katarina Vukojević, Renata Beljan Perak and Violeta Šoljić
Biomedicines 2024, 12(1), 149; https://doi.org/10.3390/biomedicines12010149 - 10 Jan 2024
Cited by 2 | Viewed by 1803
Abstract
While clear cell renal cell carcinoma (ccRCC) is curable, advanced metastatic (mRCC) remains a clinical challenge. We analyzed clinical, pathohistological, and molecular data (Receptor Interacting Protein 5—RIP5 and Vestigial Like Family Member 4—VGLL4 expression) of 55 mRCC patients treated with first-line treatment with [...] Read more.
While clear cell renal cell carcinoma (ccRCC) is curable, advanced metastatic (mRCC) remains a clinical challenge. We analyzed clinical, pathohistological, and molecular data (Receptor Interacting Protein 5—RIP5 and Vestigial Like Family Member 4—VGLL4 expression) of 55 mRCC patients treated with first-line treatment with sunitinib. The trend of linear increase in the protein expression of RIP5 was observed with the progression of tumor grade. Overall, 80% of RIP5-positive cells were in the control kidneys and high-grade mRCC. On the contrary, RIP5 displayed low expression in grade 2 mRCC (5.63%). The trend of linear decrease in the expression of VGLL4 was observed with the progression of tumor grade. The highest protein expression of VGLL4 was observed in grade 2 (87.82%) in comparison to grade 3 and 4 and control. High expression of RIP5 mRNA was associated with longer first-line overall survival and longer progression-free survival in mRCC. In addition, a high VGLL4 mRNA expression showed better overall survival in patients with ccRCC. In conclusion, high mRNA expression of RIP5 and VGLL4 are important markers of better survival rates in mRCC patients. Full article
(This article belongs to the Special Issue Recent Advances of Receptor Tyrosine Kinases in Solid Tumors)
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Review

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39 pages, 7426 KiB  
Review
Unraveling the Potential of ALK-Targeted Therapies in Non-Small Cell Lung Cancer: Comprehensive Insights and Future Directions
by Hannaneh Parvaresh, Ghazaal Roozitalab, Fatemeh Golandam, Payam Behzadi and Parham Jabbarzadeh Kaboli
Biomedicines 2024, 12(2), 297; https://doi.org/10.3390/biomedicines12020297 - 27 Jan 2024
Cited by 14 | Viewed by 6679
Abstract
Background and Objective: This review comprehensively explores the intricate landscape of anaplastic lymphoma kinase (ALK), focusing specifically on its pivotal role in non-small cell lung cancer (NSCLC). Tracing ALK’s discovery, from its fusion with nucleolar phosphoprotein (NPM)-1 in anaplastic large cell non-Hodgkin’s lymphoma [...] Read more.
Background and Objective: This review comprehensively explores the intricate landscape of anaplastic lymphoma kinase (ALK), focusing specifically on its pivotal role in non-small cell lung cancer (NSCLC). Tracing ALK’s discovery, from its fusion with nucleolar phosphoprotein (NPM)-1 in anaplastic large cell non-Hodgkin’s lymphoma (ALCL) in 1994, the review elucidates the subsequent impact of ALK gene alterations in various malignancies, including inflammatory myofibroblastoma and NSCLC. Approximately 3–5% of NSCLC patients exhibit complex ALK rearrangements, leading to the approval of six ALK-tyrosine kinase inhibitors (TKIs) by 2022, revolutionizing the treatment landscape for advanced metastatic ALK + NSCLC. Notably, second-generation TKIs such as alectinib, ceritinib, and brigatinib have emerged to address resistance issues initially associated with the pioneer ALK-TKI, crizotinib. Methods: To ensure comprehensiveness, we extensively reviewed clinical trials on ALK inhibitors for NSCLC by 2023. Additionally, we systematically searched PubMed, prioritizing studies where the terms “ALK” AND “non-small cell lung cancer” AND/OR “NSCLC” featured prominently in the titles. This approach aimed to encompass a spectrum of relevant research studies, ensuring our review incorporates the latest and most pertinent information on innovative and alternative therapeutics for ALK + NSCLC. Key Content and Findings: Beyond exploring the intricate details of ALK structure and signaling, the review explores the convergence of ALK-targeted therapy and immunotherapy, investigating the potential of immune checkpoint inhibitors in ALK-altered NSCLC tumors. Despite encouraging preclinical data, challenges observed in trials assessing combinations such as nivolumab-crizotinib, mainly due to severe hepatic toxicity, emphasize the necessity for cautious exploration of these novel approaches. Additionally, the review explores innovative directions such as ALK molecular diagnostics, ALK vaccines, and biosensors, shedding light on their promising potential within ALK-driven cancers. Conclusions: This comprehensive analysis covers molecular mechanisms, therapeutic strategies, and immune interactions associated with ALK-rearranged NSCLC. As a pivotal resource, the review guides future research and therapeutic interventions in ALK-targeted therapy for NSCLC. Full article
(This article belongs to the Special Issue Recent Advances of Receptor Tyrosine Kinases in Solid Tumors)
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