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New Insights into Targeted Therapy for Non-Small-Cell Lung Cancer: From Molecular Biology to Tumor Microenvironment

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 23296

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Special Issue Editors

Dr. Nobuhiko Seki

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Guest Editor

Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
Interests: predictive marker of targeted therapy in non-small cell lung cancer; effects of targeted therapy on the immune environment; plasma exosomes; four omics analyses (genomics, proteomics, epigenomics, and metabolomics)

Dr. Shigeru Tanzawa

E-Mail Website
Guest Editor

Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
Interests: targeted therapy in non-small cell lung cancer; acquired resistant mechanism; brain metastasis; anti-VEGF therapy

Special Issue Information

Dear Colleagues,

Molecularly targeted therapy for non-small cell lung cancer (NSCLC) has reached remarkable progress with the advent of next-generation sequencing. However, many problems remain that need to be solved.

First, there is still a lack of information on its predictive biomarkers other than driver oncogene mutations. For example, a certain number of patients do not respond to molecularly targeted therapy even if they harbor the corresponding mutations. Furthermore, biomarker studies focus mostly on genomics, but others need to be focused, including proteomics, epigenomics, and metabolomics.

Second, the relationships between molecularly targeted therapy and tumor microenvironment need to be elucidated. Recent studies have suggested that the efficacy of molecularly targeted therapy is affected by the immune environment, and conversely, molecularly targeted therapy affects the immune environment.

Third, long-term clinical benefit is inevitably compromised by multiple resistance mechanisms. Almost all molecularly targeted therapies, even if initially successful, encounter acquired resistance. Overcoming the mechanisms behind acquired resistance and establishing post-resistance treatment strategies are urgent issues.

In this Special Issue, we are looking for the latest insights into therapeutic strategies for NSCLC from the vast field of molecular biology and from the perspective of the tumor microenvironment.

Dr. Nobuhiko Seki
Dr. Shigeru Tanzawa
Guest Editors

Manuscript Submission Information

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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. Cells is an international peer-reviewed open access semimonthly 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 2700 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

non-small-cell lung cancer
molecularly targeted therapy
predictive biomarkers
genomics
proteomics
epigenomics
metabolomics
tumor microenvironment
immune environment
aquired resistance

Published Papers (10 papers)

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Research

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17 pages, 38463 KiB

Open AccessArticle

Anticancer Effects of 6-Gingerol through Downregulating Iron Transport and PD-L1 Expression in Non-Small Cell Lung Cancer Cells

by Dong Young Kang, Sanghyeon Park, Kyoung Seob Song, Se Won Bae, Jeong-Sang Lee, Kyoung-Jin Jang and Yeong-Min Park

Cells 2023, 12(22), 2628; https://doi.org/10.3390/cells12222628 - 15 Nov 2023

Cited by 1 | Viewed by 1287

Abstract

Iron homeostasis is considered a key factor in human metabolism, and abrogation in the system could create adverse effects, including cancer. Moreover, 6-gingerol is a widely used bioactive phenolic compound with anticancer activity, and studies on its exact mechanisms on non-small cell lung cancer (NSCLC) cells are still undergoing. This study aimed to find the mechanism of cell death induction by 6-gingerol in NSCLC cells. Western blotting, real-time polymerase chain reaction, and flow cytometry were used for molecular signaling studies, and invasion and tumorsphere formation assay were also used with comet assay for cellular processes. Our results show that 6-gingerol inhibited cancer cell proliferation and induced DNA damage response, cell cycle arrest, and apoptosis in NSCLC cells, and cell death induction was found to be the mitochondrial-dependent intrinsic apoptosis pathway. The role of iron homeostasis in the cell death induction of 6-gingerol was also investigated, and iron metabolism played a vital role in the anticancer ability of 6-gingerol by downregulating EGFR/JAK2/STAT5b signaling or upregulating p53 and downregulating PD-L1 expression. Also, 6-gingerol induced miR-34a and miR-200c expression, which may indicate regulation of PD-L1 expression by 6-gingerol. These results suggest that 6-gingerol could be a candidate drug against NSCLC cells and that 6-gingerol could play a vital role in cancer immunotherapy. Full article

(This article belongs to the Special Issue New Insights into Targeted Therapy for Non-Small-Cell Lung Cancer: From Molecular Biology to Tumor Microenvironment)

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Graphical abstract

10 pages, 1182 KiB

Open AccessCommunication

Implication of mTOR Signaling in NSCLC: Mechanisms and Therapeutic Perspectives

by Antonios N. Gargalionis, Kostas A. Papavassiliou and Athanasios G. Papavassiliou

Cells 2023, 12(15), 2014; https://doi.org/10.3390/cells12152014 - 7 Aug 2023

Cited by 1 | Viewed by 1111

Abstract

Mechanistic target of the rapamycin (mTOR) signaling pathway represents a central cellular kinase that controls cell survival and metabolism. Increased mTOR activation, along with upregulation of respective upstream and downstream signaling components, have been established as oncogenic features in cancer cells in various tumor types. Nevertheless, mTOR pathway therapeutic targeting has been proven to be quite challenging in various clinical settings. Non-small cell lung cancer (NSCLC) is a frequent type of solid tumor in both genders, where aberrant regulation of the mTOR pathway contributes to the development of oncogenesis, apoptosis resistance, angiogenesis, cancer progression, and metastasis. In this context, the outcome of mTOR pathway targeting in clinical trials still demonstrates unsatisfactory results. Herewith, we discuss recent findings regarding the mechanisms and therapeutic targeting of mTOR signaling networks in NSCLC, as well as future perspectives for the efficient application of treatments against mTOR and related protein molecules. Full article

(This article belongs to the Special Issue New Insights into Targeted Therapy for Non-Small-Cell Lung Cancer: From Molecular Biology to Tumor Microenvironment)

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20 pages, 7996 KiB

Open AccessArticle

The Molecular Pathogenesis of Tumor-Suppressive miR-486-5p and miR-486-3p Target Genes: GINS4 Facilitates Aggressiveness in Lung Adenocarcinoma

by Yuya Tomioka, Takayuki Suetsugu, Naohiko Seki, Kengo Tanigawa, Yoko Hagihara, Masahiro Shinmura, Shunichi Asai, Naoko Kikkawa, Hiromasa Inoue and Keiko Mizuno

Cells 2023, 12(14), 1885; https://doi.org/10.3390/cells12141885 - 18 Jul 2023

Cited by 2 | Viewed by 1383

Abstract

The involvement of passenger strands of miRNAs in the molecular pathogenesis of human cancers is a recent concept in miRNA research, and it will broaden our understanding of the molecular mechanisms of miRNA-mediated cancer. The analysis of our miRNA signature of LUAD revealed that both strands of pre-miR-486 (miR-486-5p and miR-486-3p) were downregulated in LUAD tissues. Ectopic expression of both miRNAs induced cell cycle arrest in LUAD cells, suggesting both strands of miRNAs derived from pre-miR-486 were tumor suppressive. Our in silico analysis showed a total of 99 genes may be under the control of both miRNAs in LUAD cells. Importantly, among these targets, the high expression of seven genes (MKI67, GINS4, RRM2, HELLS, MELK, TIMELESS, and SAPCD2) predicted a poorer prognosis of LUAD patients (p < 0.05). We focused on GINS4, a DNA replication complex GINS protein that plays an essential role in the initiation of DNA replication. Our functional assays showed that GINS4 was directly controlled by both strands of pre-miR-486, and its aberrant expression facilitated the aggressive behavior of LUAD cells. GINS4 is attractive as a therapeutic target for this disease. MiRNA analysis, including passenger strands, will further improve our understanding of the molecular pathogenesis of LUAD. Full article

(This article belongs to the Special Issue New Insights into Targeted Therapy for Non-Small-Cell Lung Cancer: From Molecular Biology to Tumor Microenvironment)

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12 pages, 905 KiB

Open AccessArticle

Gene Fusion Detection in NSCLC Routine Clinical Practice: Targeted-NGS or FISH?

by Lorenza Pecciarini, Emanuela Brunetto, Greta Grassini, Valeria De Pascali, Francesca Rita Ogliari, Anna Talarico, Giovanna Marra, Gilda Magliacane, Miriam Redegalli, Gianluigi Arrigoni, Chiara Lazzari, Vanesa Gregorc, Alessandra Bulotta, Claudio Doglioni and Maria Giulia Cangi

Cells 2023, 12(8), 1135; https://doi.org/10.3390/cells12081135 - 11 Apr 2023

Cited by 7 | Viewed by 1855

Abstract

The ability to identify the broadest range of targetable gene fusions is crucial to facilitate personalized therapy selection for advanced lung adenocarcinoma (LuADs) patients harboring targetable receptor tyrosine kinase (RTK) genomic alterations. In order to evaluate the most effective testing approach for LuAD targetable gene fusion detection, we analyzed 210 NSCLC selected clinical samples, comparing in situ (Fluorescence In Situ Hybridization, FISH, and ImmunoHistoChemistry, IHC) and molecular (targeted RNA Next-Generation Sequencing, NGS, and RealTime-PCR, RT-PCR) approaches. The overall concordance among these methods was high (>90%), and targeted RNA NGS was confirmed to be the most efficient technique for gene fusion identification in clinical practice, allowing the simultaneous analysis of a large set of genomic rearrangements at the RNA level. However, we observed that FISH was useful to detect targetable fusions in those samples with inadequate tissue material for molecular testing as well as in those few cases whose fusions were not identified by the RNA NGS panel. We conclude that the targeted RNA NGS analysis of LuADs allows accurate RTK fusion detection; nevertheless, standard methods such as FISH should not be dismissed, as they can crucially contribute to the completion of the molecular characterization of LuADs and, most importantly, the identification of patients as candidates for targeted therapies. Full article

(This article belongs to the Special Issue New Insights into Targeted Therapy for Non-Small-Cell Lung Cancer: From Molecular Biology to Tumor Microenvironment)

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10 pages, 4929 KiB

Open AccessCommunication

Cytological Samples: An Asset for the Diagnosis and Therapeutic Management of Patients with Lung Cancer

by Diane Frankel, Isabelle Nanni, L’Houcine Ouafik, Laurent Greillier, Hervé Dutau, Philippe Astoul, Laurent Daniel, Elise Kaspi and Patrice Roll

Cells 2023, 12(5), 754; https://doi.org/10.3390/cells12050754 - 27 Feb 2023

Cited by 1 | Viewed by 1803

Abstract

Background: Lung cancer has become the leading cause of cancer death for men and women. Most patients are diagnosed at an advanced stage when surgery is no longer a therapeutic option. At this stage, cytological samples are often the less invasive source for diagnosis and the determination of predictive markers. We assessed the ability of cytological samples to perform diagnosis, and to establish molecular profile and PD-L1 expression, which are essential for the therapeutic management of patients. Methods: We included 259 cytological samples with suspected tumor cells and assessed the ability to confirm the type of malignancy by immunocytochemistry. We summarized results of molecular testing by next generation sequencing (NGS) and PD-L1 expression from these samples. Finally, we analyzed the impact of these results in the patient management. Results: Among the 259 cytological samples, 189 concerned lung cancers. Of these, immunocytochemistry confirmed the diagnosis in 95%. Molecular testing by NGS was obtained in 93% of lung adenocarcinomas and non-small cell lung cancer. PD-L1 results were obtained in 75% of patients tested. The results obtained with cytological samples led to a therapeutic decision in 87% of patients. Conclusion: Cytological samples are obtained by minimally invasive procedures and can provide enough material for the diagnosis and therapeutic management in lung cancer patients. Full article

(This article belongs to the Special Issue New Insights into Targeted Therapy for Non-Small-Cell Lung Cancer: From Molecular Biology to Tumor Microenvironment)

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19 pages, 5113 KiB

Open AccessArticle

Silencing of circCRIM1 Drives IGF2BP1-Mediated NSCLC Immune Evasion

by Wenbei Peng, Linlin Ye, Qianqian Xue, Xiaoshan Wei, Zihao Wang, Xuan Xiang, Siyu Zhang, Pei Zhang, Haolei Wang and Qiong Zhou

Cells 2023, 12(2), 273; https://doi.org/10.3390/cells12020273 - 10 Jan 2023

Cited by 3 | Viewed by 2010

Abstract

Objectives: Circular RNAs (circRNAs) have been found to have significant impacts on non-small cell lung cancer (NSCLC) progression through various mechanisms. However, the mechanism of circRNAs modulating tumor immune evasion in NSCLC has yet to be well-revealed. Materials and Methods: Through analyzing the expression profiles of circRNAs in NSCLC tissues, RNA FISH, pull-down assay, mass spectrometry analysis, and RIP, circCRIM1 was identified, and its interaction with IGF2BP1 was confirmed. The effects of circCRIM1 on modulating tumor immune evasion were explored via co-culture in vitro and in tumor xenograft models. Subsequently, we evaluated the regulatory effects of circCRIM1 on IGF2BP1 and screened its target genes through RNA sequencing. Finally, we explored the underlying molecular mechanisms that circCRIM1 could regulate the stability of target mRNA. Results: circCRIM1 was downregulated in NSCLC, and its expression was positively correlated with favorable prognoses. Furthermore, circCRIM1 was more stable than its linear transcript and was mainly localized in the cytoplasm. Mechanistically, circCRIM1 destabilized HLA-F mRNA via competitive binding to IGF2BP1. Importantly, the overexpression of circCRIM1 suppressed the immune evasion of NSCLC and promoted the expressions of Granzyme B, IFN-γ, and TNF-α of CD8+ T and NK cell in vitro co-culture assays and tumor xenograft models. Conclusions: This study identifies circCRIM1 as a new tumor suppressor that inhibits tumor immune evasion through a competitive combination with IGF2BP1 to destabilize HLA-F mRNA. Full article

(This article belongs to the Special Issue New Insights into Targeted Therapy for Non-Small-Cell Lung Cancer: From Molecular Biology to Tumor Microenvironment)

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13 pages, 10382 KiB

Open AccessArticle

Cyclin-Dependent Kinase Subunit 2 (CKS2) as a Prognostic Marker for Stages I–III Invasive Non-Mucinous Lung Adenocarcinoma and Its Role in Affecting Drug Sensitivity

by Junkai Feng, Menglong Hu, Zongkuo Li, Guiming Hu, Yuting Han, Yan Zhang, Min Zhang and Jingli Ren

Cells 2022, 11(16), 2611; https://doi.org/10.3390/cells11162611 - 22 Aug 2022

Cited by 2 | Viewed by 2011

Abstract

With the aim of improving the prognosis of patients with lung adenocarcinoma (LUAD), we identified the biomarker related to the sensitivity of patients to chemotherapy drugs and explored the potential mechanisms. As a cell cycle-related protein, CKS2 has an essential role to play in tumor progression and prognosis. CKS2 expression was measured using TCGA RNA-sequencing data and immunohistochemistry. The sensitivity data of tumor cells to chemotherapeutic drugs for lung cancer was acquired from the Cancer Therapeutics Response Portal (CTRP) database. A range of bioinformatics methods was used to explore the mechanisms of CKS2 upregulation. The biological functions of CKS2 were predicted using GO and KEGG enrichment analysis, as well as GSEA. CKS2 expression was up-regulated in stages I–III invasive non-mucinous lung adenocarcinoma and varied significantly between various histological subtypes. High CKS2 expression worsened the prognosis of patients. The CKS2 expression level was linked to the sensitivity of LUAD cells to carboplatin and paclitaxel. CKS2 upregulation was associated with the immune microenvironment, mRNA methylation, and competing endogenous RNAs (ceRNAs). CKS2 can serve as a diagnostic and prognostic biomarker for stages I–III invasive non-mucinous lung adenocarcinoma and modulate the effect of paclitaxel and carboplatin by regulating microtubule binding and influencing carboplatin binding to DNA. Full article

(This article belongs to the Special Issue New Insights into Targeted Therapy for Non-Small-Cell Lung Cancer: From Molecular Biology to Tumor Microenvironment)

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Review

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26 pages, 1343 KiB

Open AccessReview

KRAS-Mutant Lung Cancer: Targeting Molecular and Immunologic Pathways, Therapeutic Advantages and Restrictions

by Nastaran Karimi and Seyed Javad Moghaddam

Cells 2023, 12(5), 749; https://doi.org/10.3390/cells12050749 - 26 Feb 2023

Cited by 6 | Viewed by 5013

Abstract

RAS mutations are among the most common oncogenic mutations in human cancers. Among RAS mutations, KRAS has the highest frequency and is present in almost 30% of non-small-cell lung cancer (NSCLC) patients. Lung cancer is the number one cause of mortality among cancers as a consequence of outrageous aggressiveness and late diagnosis. High mortality rates have been the reason behind numerous investigations and clinical trials to discover proper therapeutic agents targeting KRAS. These approaches include the following: direct KRAS targeting; synthetic lethality partner inhibitors; targeting of KRAS membrane association and associated metabolic rewiring; autophagy inhibitors; downstream inhibitors; and immunotherapies and other immune-modalities such as modulating inflammatory signaling transcription factors (e.g., STAT3). The majority of these have unfortunately encountered limited therapeutic outcomes due to multiple restrictive mechanisms including the presence of co-mutations. In this review we plan to summarize the past and most recent therapies under investigation, along with their therapeutic success rate and potential restrictions. This will provide useful information to improve the design of novel agents for treatment of this deadly disease. Full article

(This article belongs to the Special Issue New Insights into Targeted Therapy for Non-Small-Cell Lung Cancer: From Molecular Biology to Tumor Microenvironment)

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14 pages, 313 KiB

Open AccessReview

Immunotherapy in Non-Small-Cell Lung Cancer Patients with Driver Alterations: A New Strategy?

by Natalia Krzyżanowska, Paweł Krawczyk, Kamila Wojas-Krawczyk, Tomasz Kucharczyk and Janusz Milanowski

Cells 2022, 11(20), 3280; https://doi.org/10.3390/cells11203280 - 18 Oct 2022

Cited by 9 | Viewed by 2131

Abstract

For many years, researchers have been trying to develop the most effective ways to fight lung cancer, which is the cause of the largest number of cancer-related deaths among men and women worldwide. The most advanced treatments for nearly all non-small-cell lung cancer (NSCLC) types include immunotherapy with immune checkpoint inhibitors (ICIs), mainly anti-programmed death 1/anti-programmed death ligand 1 monoclonal antibodies (anti-PD-1/PD-L1 mAbs) in monotherapy or in combination with other strategies. Despite significant advances, long survival is not achievable in most cases, so new solutions are constantly being sought. One of the questions raised by oncologists is the efficacy of ICIs in patients with molecular driver alterations, especially when the possibilities of using molecularly targeted therapies are exhausted (e.g., due to resistance to tyrosine kinase inhibitors). There are studies investigating this problem, but it is still poorly described. Among probable immunotherapy’ failures reasons, low immunogenicity of tumors with one driver mutation is listed. Nevertheless, in some cases, the therapy is efficient, and more research is required to establish the management of NSCLC patients with oncogenic driver abnormalities. The aim of this article is to review current discoveries in this matter. Full article

(This article belongs to the Special Issue New Insights into Targeted Therapy for Non-Small-Cell Lung Cancer: From Molecular Biology to Tumor Microenvironment)

17 pages, 855 KiB

Open AccessReview

Interleukin-11: A Potential Biomarker and Molecular Therapeutic Target in Non-Small Cell Lung Cancer

by Jason Hongting Leung, Benjamin Ng and Wei-Wen Lim

Cells 2022, 11(14), 2257; https://doi.org/10.3390/cells11142257 - 21 Jul 2022

Cited by 7 | Viewed by 3469

Abstract

Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer and is a fast progressive disease when left untreated. Identification of potential biomarkers in NSCLC is an ongoing area of research that aims to detect, diagnose, and prognosticate patients early to optimize treatment. We review the role of interleukin-11 (IL11), a stromal-cell derived pleiotropic cytokine with profibrotic and cellular remodeling properties, as a potential biomarker in NSCLC. This review identifies the need for biomarkers in NSCLC, the potential sources of IL11, and summarizes the available information leveraging upon published literature, publicly available datasets, and online tools. We identify accumulating evidence suggesting IL11 to be a potential biomarker in NSCLC patients. Further in-depth studies into the pathophysiological effects of IL11 on stromal-tumor interaction in NSCLC are warranted and current available literature highlights the potential value of IL11 detection as a diagnostic and prognostic biomarker in NSCLC. Full article

(This article belongs to the Special Issue New Insights into Targeted Therapy for Non-Small-Cell Lung Cancer: From Molecular Biology to Tumor Microenvironment)

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