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Editorial

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3 pages, 191 KiB

Open AccessEditorial

The Different Roles of MET in the Development and Treatment of Cancer

by Jens Mollerup and Jan Trøst Jørgensen

Cancers 2023, 15(20), 5087; https://doi.org/10.3390/cancers15205087 - 21 Oct 2023

Viewed by 1078

Abstract

This Special Issue features contributions from leading international researchers in the field of MET (hepatocyte growth factor (HGF) receptor) biology and therapeutics [...] Full article

(This article belongs to the Special Issue Roles of MET in Cancer Development and Treatment)

Research

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25 pages, 4741 KiB

Open AccessArticle

Rilotumumab Resistance Acquired by Intracrine Hepatocyte Growth Factor Signaling

by Fabiola Cecchi, Karen Rex, Joanna Schmidt, Cathy D. Vocke, Young H. Lee, Sandra Burkett, Daniel Baker, Michael A. Damore, Angela Coxon, Teresa L. Burgess and Donald P. Bottaro

Cancers 2023, 15(2), 460; https://doi.org/10.3390/cancers15020460 - 11 Jan 2023

Cited by 4 | Viewed by 2087

Abstract

Drug resistance is a long-standing impediment to effective systemic cancer therapy and acquired drug resistance is a growing problem for molecularly-targeted therapeutics that otherwise have shown unprecedented successes in disease control. The hepatocyte growth factor (HGF)/Met receptor pathway signaling is frequently involved in [...] Read more.

Drug resistance is a long-standing impediment to effective systemic cancer therapy and acquired drug resistance is a growing problem for molecularly-targeted therapeutics that otherwise have shown unprecedented successes in disease control. The hepatocyte growth factor (HGF)/Met receptor pathway signaling is frequently involved in cancer and has been a subject of targeted drug development for nearly 30 years. To anticipate and study specific resistance mechanisms associated with targeting this pathway, we engineered resistance to the HGF-neutralizing antibody rilotumumab in glioblastoma cells harboring autocrine HGF/Met signaling, a frequent abnormality of this brain cancer in humans. We found that rilotumumab resistance was acquired through an unusual mechanism comprising dramatic HGF overproduction and misfolding, endoplasmic reticulum (ER) stress-response signaling and redirected vesicular trafficking that effectively sequestered rilotumumab and misfolded HGF from native HGF and activated Met. Amplification of MET and HGF genes, with evidence of rapidly acquired intron-less, reverse-transcribed copies in DNA, was also observed. These changes enabled persistent Met pathway activation and improved cell survival under stress conditions. Point mutations in the HGF pathway or other complementary or downstream growth regulatory cascades that are frequently associated with targeted drug resistance in other prevalent cancer types were not observed. Although resistant cells were significantly more malignant, they retained sensitivity to Met kinase inhibition and acquired sensitivity to inhibition of ER stress signaling and cholesterol biosynthesis. Defining this mechanism reveals details of a rapidly acquired yet highly-orchestrated multisystem route of resistance to a selective molecularly-targeted agent and suggests strategies for early detection and effective intervention. Full article

(This article belongs to the Special Issue Roles of MET in Cancer Development and Treatment)

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15 pages, 1674 KiB

Open AccessArticle

Longitudinal Plasma Proteomics-Derived Biomarkers Predict Response to MET Inhibitors for MET-Dysregulated NSCLC

by Guang-Ling Jie, Lun-Xi Peng, Mei-Mei Zheng, Hao Sun, Song-Rong Wang, Si-Yang Maggie Liu, Kai Yin, Zhi-Hong Chen, Hong-Xia Tian, Jin-Ji Yang, Xu-Chao Zhang, Hai-Yan Tu, Qing Zhou, Catherine C. L. Wong and Yi-Long Wu

Cancers 2023, 15(1), 302; https://doi.org/10.3390/cancers15010302 - 1 Jan 2023

Cited by 2 | Viewed by 3262

Abstract

MET inhibitors have shown promising efficacy for MET-dysregulated non-small cell lung cancer (NSCLC). However, quite a few patients cannot benefit from it due to the lack of powerful biomarkers. This study aims to explore the potential role of plasma proteomics-derived biomarkers for patients [...] Read more.

MET inhibitors have shown promising efficacy for MET-dysregulated non-small cell lung cancer (NSCLC). However, quite a few patients cannot benefit from it due to the lack of powerful biomarkers. This study aims to explore the potential role of plasma proteomics-derived biomarkers for patients treated with MET inhibitors using mass spectrometry. We analyzed the plasma proteomics from patients with MET dysregulation (including MET amplification and MET overexpression) treated with MET inhibitors. Thirty-three MET-dysregulated NSCLC patients with longitudinal 89 plasma samples were included. We classified patients into the PD group and non-PD group based on clinical response. The baseline proteomic profiles of patients in the PD group were distinct from those in the non-PD group. Through protein screening, we found that a four-protein signature (MYH9, GNB1, ALOX12B, HSD17B4) could predict the efficacy of patients treated with MET inhibitors, with an area under the curve (AUC) of 0.93, better than conventional fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC) tests. In addition, combining the four-protein signature with FISH or IHC test could also reach higher predictive performance. Further, the combined signature could predict progression-free survival for MET-dysregulated NSCLC (p < 0.001). We also validated the performance of the four-protein signature in another cohort of plasma using an enzyme-linked immunosorbent assay. In conclusion, the four plasma protein signature (MYH9, GNB1, ALOX12B, and HSD17B4 proteins) might play a substitutable or complementary role to conventional MET FISH or IHC tests. This exploration will help select patients who may benefit from MET inhibitors. Full article

(This article belongs to the Special Issue Roles of MET in Cancer Development and Treatment)

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13 pages, 1361 KiB

Open AccessArticle

Molecular Characteristics of Radon Associated Lung Cancer Highlights MET Alterations

by Gabriele Gamerith, Marcel Kloppenburg, Finn Mildner, Arno Amann, Sabine Merkelbach-Bruse, Carina Heydt, Janna Siemanowski, Reinhard Buettner, Michael Fiegl, Claudia Manzl and Georg Pall

Cancers 2022, 14(20), 5113; https://doi.org/10.3390/cancers14205113 - 19 Oct 2022

Cited by 2 | Viewed by 1793

Abstract

Effective targeted treatment strategies resulted from molecular profiling of lung cancer with distinct prevalent mutation profiles in smokers and non-smokers. Although Rn is the second most important risk factor, data for Rn-dependent driver events are limited. Therefore, a Rn-exposed cohort of lung cancer [...] Read more.

Effective targeted treatment strategies resulted from molecular profiling of lung cancer with distinct prevalent mutation profiles in smokers and non-smokers. Although Rn is the second most important risk factor, data for Rn-dependent driver events are limited. Therefore, a Rn-exposed cohort of lung cancer patients was screened for oncogenic drivers and their survival and genetic profiles were compared with data of the average regional population. Genetic alterations were analysed in 20 Rn-exposed and 22 histologically matched non-Rn exposed LC patients using targeted Next generation sequencing (NGS) and Fluorescence In Situ Hybridization (FISH). Sufficient material and sample quality could be obtained in 14/27 non-exposed versus 17/22 Rn-exposed LC samples. Survival was analysed in comparison to a histologically and stage-matched regional non-exposed lung cancer cohort (n = 51) for hypothesis generating. Median overall survivals were 83.02 months in the Rn-exposed and 38.7 months in the non-exposed lung cancer cohort (p = 0.22). Genetic alterations of both patient cohorts were in high concordance, except for an increase in MET alterations and a decrease in TP53 mutations in the Rn-exposed patients in this small hypothesis generating study. Full article

(This article belongs to the Special Issue Roles of MET in Cancer Development and Treatment)

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11 pages, 2883 KiB

Open AccessArticle

Identification of Novel MET Exon 14 Skipping Variants in Non-Small Cell Lung Cancer Patients: A Prototype Workflow Involving in Silico Prediction and RT-PCR

by Riku Das, Maureen A. Jakubowski, Jessica Spildener and Yu-Wei Cheng

Cancers 2022, 14(19), 4814; https://doi.org/10.3390/cancers14194814 - 1 Oct 2022

Cited by 3 | Viewed by 2975

Abstract

Background and aims: The MET exon 14 skipping (METex14) is an oncogenic driver mutation that provides a therapeutic opportunity in non-small cell lung cancer (NSCLCs) patients. This event often results from sequence changes at the MET canonical splicing sites. We characterize two novel [...] Read more.

Background and aims: The MET exon 14 skipping (METex14) is an oncogenic driver mutation that provides a therapeutic opportunity in non-small cell lung cancer (NSCLCs) patients. This event often results from sequence changes at the MET canonical splicing sites. We characterize two novel non-canonical splicing site variants of MET that produce METex14. Materials and Methods: Two variants were identified in three advanced-stage NSCLC patients in a next-generation sequencing panel. The potential impact on splicing was predicted using in silico tools. METex14 mutation was confirmed using reverse transcription (RT)-PCR and a Sanger sequencing analysis on RNA extracted from stained cytology smears. Results: The interrogated MET (RefSeq ID NM_000245.3) variants include a single nucleotide substitution, c.3028+3A>T, in intron 14 and a deletion mutation, c.3012_3028del, in exon 14. The in silico prediction analysis exhibited reduced splicing strength in both variants compared with the MET normal transcript. The RT-PCR and subsequent Sanger sequencing analyses confirmed METex14 skipping in all three patients carrying these variants. Conclusion: This study reveals two non-canonical MET splice variants that cause exon 14 skipping, concurrently also proposes a clinical workflow for the classification of such non-canonical splicing site variants detected by routine DNA-based NGS test. It shows the usefulness of in silico prediction to identify potential METex14 driver mutation and exemplifies the opportunity of routine cytology slides for RNA-based testing. Full article

(This article belongs to the Special Issue Roles of MET in Cancer Development and Treatment)

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Review

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14 pages, 698 KiB

Open AccessReview

Targeting MET Amplification: Opportunities and Obstacles in Therapeutic Approaches

by Yuichi Kumaki, Goshi Oda and Sadakatsu Ikeda

Cancers 2023, 15(18), 4552; https://doi.org/10.3390/cancers15184552 - 14 Sep 2023

Cited by 4 | Viewed by 2813

Abstract

The MET gene plays a vital role in cellular proliferation, earning it recognition as a principal oncogene. Therapies that target MET amplification have demonstrated promising results both in preclinical models and in specific clinical cases. A significant obstacle to these therapies is the [...] Read more.

The MET gene plays a vital role in cellular proliferation, earning it recognition as a principal oncogene. Therapies that target MET amplification have demonstrated promising results both in preclinical models and in specific clinical cases. A significant obstacle to these therapies is the ability to distinguish between focal amplification and polysomy, a task for which simple MET copy number measurement proves insufficient. To effectively differentiate between the two, it is crucial to utilize comparative measures, including in situ hybridization (ISH) with the centromere or next generation sequencing (NGS) with adjacent genes. Despite the promising potential of MET amplification treatment, the judicious selection of patients is paramount to maximize therapeutic efficacy. The effectiveness of MET inhibitors can fluctuate depending on the extent of MET amplification. Future research must seek to establish the ideal threshold value for MET amplification, identify the most efficacious combination therapies, and innovate new targeted treatments for patients exhibiting MET amplification. Full article

(This article belongs to the Special Issue Roles of MET in Cancer Development and Treatment)

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19 pages, 870 KiB

Open AccessReview

The Development and Role of Capmatinib in the Treatment of MET-Dysregulated Non-Small Cell Lung Cancer—A Narrative Review

by Robert Hsu, David J. Benjamin and Misako Nagasaka

Cancers 2023, 15(14), 3561; https://doi.org/10.3390/cancers15143561 - 10 Jul 2023

Cited by 5 | Viewed by 3638

Abstract

Non-small cell lung cancer (NSCLC) is a leading cause of death, but over the past decade, there has been tremendous progress in the field with new targeted therapies. The mesenchymal–epithelial transition factor (MET) proto-oncogene has been implicated in multiple solid tumors, [...] Read more.

Non-small cell lung cancer (NSCLC) is a leading cause of death, but over the past decade, there has been tremendous progress in the field with new targeted therapies. The mesenchymal–epithelial transition factor (MET) proto-oncogene has been implicated in multiple solid tumors, including NSCLC, and dysregulation in NSCLC from MET can present most notably as MET exon 14 skipping mutation and amplification. From this, MET tyrosine kinase inhibitors (TKIs) have been developed to treat this dysregulation despite challenges with efficacy and reliable biomarkers. Capmatinib is a Type Ib MET TKI first discovered in 2011 and was FDA approved in August 2022 for advanced NSCLC with MET exon 14 skipping mutation. In this narrative review, we discuss preclinical and early-phase studies that led to the GEOMETRY mono-1 study, which showed beneficial efficacy in MET exon 14 skipping mutations, leading to FDA approval of capmatinib along with Foundation One CDx assay as its companion diagnostic assay. Current and future directions of capmatinib are focused on improving the efficacy, overcoming the resistance of capmatinib, and finding approaches for new indications of capmatinib such as acquired MET amplification from epidermal growth factor receptor (EGFR) TKI resistance. Clinical trials now involve combination therapy with capmatinib, including amivantamab, trametinib, and immunotherapy. Furthermore, new drug agents, particularly antibody–drug conjugates, are being developed to help treat patients with acquired resistance from capmatinib and other TKIs. Full article

(This article belongs to the Special Issue Roles of MET in Cancer Development and Treatment)

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14 pages, 291 KiB

Open AccessReview

The Role of MET in Resistance to EGFR Inhibition in NSCLC: A Review of Mechanisms and Treatment Implications

by Susan L. Feldt and Christine M. Bestvina

Cancers 2023, 15(11), 2998; https://doi.org/10.3390/cancers15112998 - 31 May 2023

Cited by 6 | Viewed by 2871

Abstract

Utilizing targeted therapy against activating mutations has opened a new era of treatment paradigms for patients with advanced non-small cell lung cancer (NSCLC). For patients with epidermal growth factor (EGFR)-mutated cancers, EGFR inhibitors, including the third-generation tyrosine kinase inhibitor (TKI) osimertinib, significantly [...] Read more.

Utilizing targeted therapy against activating mutations has opened a new era of treatment paradigms for patients with advanced non-small cell lung cancer (NSCLC). For patients with epidermal growth factor (EGFR)-mutated cancers, EGFR inhibitors, including the third-generation tyrosine kinase inhibitor (TKI) osimertinib, significantly prolong progression-free survival and overall survival, and are the current standard of care. However, progression after EGFR inhibition invariably occurs, and further study has helped elucidate mechanisms of resistance. Abnormalities in the mesenchymal-epithelial transition (MET) oncogenic pathway have been implicated as common alterations after progression, with MET amplification as one of the most frequent mechanisms. Multiple drugs with inhibitory activity against MET, including TKIs, antibodies, and antibody–drug conjugates, have been developed and studied in advanced NSCLC. Combining MET and EGFR is a promising treatment strategy for patients found to have a MET-driven resistance mechanism. Combination TKI therapy and EGFR-MET bispecific antibodies have shown promising anti-tumor activity in early clinical trials. Future study including ongoing large-scale trials of combination EGFR-MET inhibition will help clarify if targeting this mechanism behind EGFR resistance will have meaningful clinical benefit for patients with advanced EGFR-mutated NSCLC. Full article

(This article belongs to the Special Issue Roles of MET in Cancer Development and Treatment)

14 pages, 785 KiB

Open AccessReview

Overview of Molecular Detection Technologies for MET in Lung Cancer

by Carina Heydt, Michaela Angelika Ihle and Sabine Merkelbach-Bruse

Cancers 2023, 15(11), 2932; https://doi.org/10.3390/cancers15112932 - 26 May 2023

Cited by 7 | Viewed by 2655

Abstract

MET tyrosine kinase receptor pathway activation has become an important actionable target in solid tumors. Aberrations in the MET proto-oncogene, including MET overexpression, the activation of MET mutations, MET mutations that lead to MET exon 14 skipping, MET gene amplifications, and MET fusions, [...] Read more.

MET tyrosine kinase receptor pathway activation has become an important actionable target in solid tumors. Aberrations in the MET proto-oncogene, including MET overexpression, the activation of MET mutations, MET mutations that lead to MET exon 14 skipping, MET gene amplifications, and MET fusions, are known to be primary and secondary oncogenic drivers in cancer; these aberrations have evolved as predictive biomarkers in clinical diagnostics. Thus, the detection of all known MET aberrations in daily clinical care is essential. In this review, current molecular technologies for the detection of the different MET aberrations are highlighted, including the benefits and drawbacks. In the future, another focus will be on the standardization of detection technologies for the delivery of reliable, quick, and affordable tests in clinical molecular diagnostics. Full article

(This article belongs to the Special Issue Roles of MET in Cancer Development and Treatment)

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13 pages, 744 KiB

Open AccessReview

The Role of cMET in Gastric Cancer—A Review of the Literature

by Filip Van Herpe and Eric Van Cutsem

Cancers 2023, 15(7), 1976; https://doi.org/10.3390/cancers15071976 - 26 Mar 2023

Cited by 9 | Viewed by 3349

Abstract

Gastric cancer (GC) is an important cause of cancer worldwide with over one million new cases yearly. The vast majority of cases present in stage IV disease, and it still bears a poor prognosis. However, since 2010, progress has been made with the [...] Read more.

Gastric cancer (GC) is an important cause of cancer worldwide with over one million new cases yearly. The vast majority of cases present in stage IV disease, and it still bears a poor prognosis. However, since 2010, progress has been made with the introduction of targeted therapies against HER2 and with checkpoint inhibitors (PDL1). More agents interfering with other targets (FGFR2B, CLDN18.2) are being investigated. cMET is a less frequent molecular target that has been studied for gastric cancer. It is a proto-oncogene that leads to activation of the MAPK pathway and the PI3K pathway, which is responsible for activating the MTOR pathway. The prevalence of cMET is strongly debated as different techniques are being used to detect MET-driven tumors. Because of the difference in diagnostic assays, selecting patients who benefit from cMET inhibitors is difficult. In this review, we discuss the pathway of cMET, its clinical significance and the different diagnostic assays that are currently used, such as immunohistochemy (IHC), fluorescence in situ hybridization (FISH), the H-score and next-generation sequencing (NGS). Next, we discuss all the current data on cMET inhibitors in gastric cancer. Since the data on cMET inhibitors are very heterogenous, it is difficult to provide a general consensus on the outcome, as inclusion criteria differ between trials. Diagnosing cMET-driven gastric tumors is difficult, and potentially the only accurate determination of cMET overexpression/amplification may be next-generation sequencing (NGS). Full article

(This article belongs to the Special Issue Roles of MET in Cancer Development and Treatment)

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15 pages, 695 KiB

Open AccessReview

MET Amplification as a Resistance Driver to TKI Therapies in Lung Cancer: Clinical Challenges and Opportunities

by Kang Qin, Lingzhi Hong, Jianjun Zhang and Xiuning Le

Cancers 2023, 15(3), 612; https://doi.org/10.3390/cancers15030612 - 18 Jan 2023

Cited by 21 | Viewed by 6857

Abstract

Targeted therapy has emerged as an important pillar for the standard of care in oncogene-driven non-small cell lung cancer (NSCLC), which significantly improved outcomes of patients whose tumors harbor oncogenic driver mutations. However, tumors eventually develop resistance to targeted drugs, and mechanisms of [...] Read more.

Targeted therapy has emerged as an important pillar for the standard of care in oncogene-driven non-small cell lung cancer (NSCLC), which significantly improved outcomes of patients whose tumors harbor oncogenic driver mutations. However, tumors eventually develop resistance to targeted drugs, and mechanisms of resistance can be diverse. MET amplification has been proven to be a driver of resistance to tyrosine kinase inhibitor (TKI)-treated advanced NSCLC with its activation of EGFR, ALK, RET, and ROS-1 alterations. The combined therapy of MET-TKIs and EGFR-TKIs has shown outstanding clinical efficacy in EGFR-mutated NSCLC with secondary MET amplification-mediated resistance in a series of clinical trials. In this review, we aimed to clarify the underlying mechanisms of MET amplification-mediated resistance to tyrosine kinase inhibitors, discuss the ways and challenges in the detection and diagnosis of MET amplifications in patients with metastatic NSCLC, and summarize the recently published clinical data as well as ongoing trials of new combination strategies to overcome MET amplification-mediated TKI resistance. Full article

(This article belongs to the Special Issue Roles of MET in Cancer Development and Treatment)

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19 pages, 1575 KiB

Open AccessReview

Landscape of Savolitinib Development for the Treatment of Non-Small Cell Lung Cancer with MET Alteration—A Narrative Review

by Xiaokuan Zhu, Yao Lu and Shun Lu

Cancers 2022, 14(24), 6122; https://doi.org/10.3390/cancers14246122 - 12 Dec 2022

Cited by 11 | Viewed by 4047

Abstract

Non-small cell lung cancer (NSCLC) is increasingly being treated with targeted therapies. Savolitinib (Orpathys^®) is highly selective mesenchymal epithelial transition (MET)–tyrosine kinase inhibitor (TKI), which is conditionally approved in China for advanced NSCLC with MET exon 14 skipping mutations (MET [...] Read more.

Non-small cell lung cancer (NSCLC) is increasingly being treated with targeted therapies. Savolitinib (Orpathys^®) is highly selective mesenchymal epithelial transition (MET)–tyrosine kinase inhibitor (TKI), which is conditionally approved in China for advanced NSCLC with MET exon 14 skipping mutations (METex14). This article summarizes the clinical development of savolitinib, as a monotherapy in NSCLC with METex14 mutation and in combination with epidermal growth factor receptor (EGFR) inhibitor in post EGFR–TKI resistance NSCLC due to MET-based acquired resistance. Preclinical models demonstrated anti-tumor activities in MET-driven cancer cell line and xenograft tumor models. The Phase Ia/Ib study established an optimized, recommended phase II dose in Chinese NSCLC patients, while TATTON study of savolitinib plus osimertinib in patients with EGFR mutant, MET-amplified and TKI-progressed NSCLC showed beneficial efficacy with acceptable safety profile. In a pivotal phase II study, Chinese patients with pulmonary sarcomatoid carcinoma, brain metastasis and other NSCLC subtype positive for METex14 mutation showed notable responses and acceptable safety profile with savolitinib. Currently, results from ongoing clinical trials are eagerly anticipated to confirm the efficacious and safety benefits of savolitinib as monotherapy and in combination with EGFR–TKI in acquired resistance setting in advanced NSCLC and its subtypes with MET alterations. Full article

(This article belongs to the Special Issue Roles of MET in Cancer Development and Treatment)

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11 pages, 664 KiB

Open AccessReview

Companion Diagnostics and Predictive Biomarkers for MET-Targeted Therapy in NSCLC

by Jan Trøst Jørgensen and Jens Mollerup

Cancers 2022, 14(9), 2150; https://doi.org/10.3390/cancers14092150 - 26 Apr 2022

Cited by 16 | Viewed by 4591

Abstract

Dysregulation of the MET tyrosine kinase receptor is a known oncogenic driver, and multiple genetic alterations can lead to a clinically relevant oncogenesis. Currently, a number of drugs targeting MET are under development as potential therapeutics for different cancer indications, including non-small cell [...] Read more.

Dysregulation of the MET tyrosine kinase receptor is a known oncogenic driver, and multiple genetic alterations can lead to a clinically relevant oncogenesis. Currently, a number of drugs targeting MET are under development as potential therapeutics for different cancer indications, including non-small cell lung cancer (NSCLC). However, relatively few of these drugs have shown sufficient clinical activity and obtained regulatory approval. One of the reasons for this could be the lack of effective predictive biomarkers to select the right patient populations for treatment. So far, capmatinib is the only MET-targeted drug approved with a companion diagnostic (CDx) assay, which is indicated for the treatment of metastatic NSCLC in patients having a mutation resulting in MET exon 14 skipping. An alternative predictive biomarker for MET therapy is MET amplification, which has been identified as a resistance mechanism in patients with EGFR-mutated NSCLC. Results obtained from different clinical trials seem to indicate that the MET/CEP7 ratio detected by FISH possesses the best predictive properties, likely because this method excludes MET amplification caused by polysomy. In this article, the concept of CDx assays will be discussed, with a focus on the currently FDA-approved MET targeted therapies for the treatment of NSCLC. Full article

(This article belongs to the Special Issue Roles of MET in Cancer Development and Treatment)

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Other

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34 pages, 4205 KiB

Open AccessSystematic Review

A Systematic Review of Mesenchymal Epithelial Transition Factor (MET) and Its Impact in the Development and Treatment of Non-Small-Cell Lung Cancer

by Embla Bodén, Fanny Sveréus, Franziska Olm and Sandra Lindstedt

Cancers 2023, 15(15), 3827; https://doi.org/10.3390/cancers15153827 - 27 Jul 2023

Cited by 2 | Viewed by 2014

Abstract

Lung cancer represents the leading cause of annual cancer-related deaths worldwide, accounting for 12.9%. The available treatment options for patients who experience disease progression remain limited. Targeted therapeutic approaches are promising but further understanding of the role of genetic alterations in tumorigenesis is [...] Read more.

Lung cancer represents the leading cause of annual cancer-related deaths worldwide, accounting for 12.9%. The available treatment options for patients who experience disease progression remain limited. Targeted therapeutic approaches are promising but further understanding of the role of genetic alterations in tumorigenesis is imperative. The MET gene has garnered great interest in this regard. The aim of this systematic review was to analyze the findings from multiple studies to provide a comprehensive and unbiased summary of the evidence. A systematic search was conducted in the reputable scientific databases Embase and PubMed, leading to the inclusion of twenty-two articles, following the PRISMA guidelines, elucidating the biological role of MET in lung cancer and targeted therapies. The systematic review was registered in PROSPERO with registration ID: CRD42023437714. MET mutations were detected in 7.6–11.0% of cases while MET gene amplification was observed in 3.9–22.0%. Six studies showed favorable treatment outcomes utilizing MET inhibitors compared to standard treatment or placebo, with increases in PFS and OS ranging from 0.9 to 12.4 and 7.2 to 24.2 months, respectively, and one study reporting an increase in ORR by 17.3%. Furthermore, patients with a higher mutational burden may derive greater benefit from treatment with MET tyrosine kinase inhibitors (TKIs) than those with a lower mutational burden. Conversely, two studies reported no beneficial effect from adjunctive treatment with a MET targeted therapy. Given these findings, there is an urgent need to identify effective therapeutic strategies specifically targeting the MET gene in lung cancer patients. Full article

(This article belongs to the Special Issue Roles of MET in Cancer Development and Treatment)

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