Lung Cancer with MET exon 14 Skipping Mutation: Genetic Feature, Current Treatments, and Future Challenges

Fujino, Toshio; Suda, Kenichi; Mitsudomi, Tetsuya

doi:10.2147/lctt.s269307

Cited by 51 publications

(41 citation statements)

References 89 publications

(153 reference statements)

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“…However, drugs targeting MET in patients in clinical trials yielded positive but puzzling results ( Paik et al, 2015 , 2020 ; Engstrom et al, 2017 ; Klempner et al, 2017 ; Hu et al, 2018 ; Landi et al, 2019 ; Moro-Sibilot et al, 2019 ; Drilon et al, 2020 ; Wolf et al, 2020 ). Specifically, only half of the patients harbouring MET∆14 benefited from MET-targeted therapies, suggesting that there are critical aspects of MET∆14 that remained unaccounted for Salgia et al (2020) and Fujino et al (2021) .…”

Section: Introductionmentioning

confidence: 99%

MET∆14 promotes a ligand-dependent, AKT-driven invasive growth

et al. 2022

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MET is an oncogene encoding the tyrosine kinase receptor for hepatocyte growth factor (HGF). Upon ligand binding, MET activates multiple signal transducers, including PI3K/AKT, STAT3, and MAPK. When mutated or amplified, MET becomes a “driver” for the onset and progression of cancer. The most frequent mutations in the MET gene affect the splicing sites of exon 14, leading to the deletion of the receptor’s juxtamembrane domain (MET∆14). It is currently believed that, as in gene amplification, MET∆14 kinase is constitutively active. Our analysis of MET in carcinoma cell lines showed that MET∆14 strictly depends on HGF for kinase activation. Compared with wt MET, ∆14 is sensitive to lower HGF concentrations, with more sustained kinase response. Using three different models, we have demonstrated that MET∆14 activation leads to robust phosphorylation of AKT, leading to a distinctive transcriptomic signature. Functional studies revealed that ∆14 activation is predominantly responsible for enhanced protection from apoptosis and cellular migration. Thus, the unique HGF-dependent ∆14 oncogenic activity suggests consideration of HGF in the tumour microenvironment to select patients for clinical trials.

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Section: Introductionmentioning

confidence: 99%

MET∆14 promotes a ligand-dependent, AKT-driven invasive growth

et al. 2022

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“…METex14 has been identi ed in about 3% of lung NSCLCs and other solid tumours like breast cancer and glioblastoma. In 2020 and 2021, two MET-inhibitors; capmatinib and tepotinib, were approved for use as monotherapies in NSCLC patients carrying METex14 (37). Here we are the rst to report the METex14 alteration in treatment-naïve UrC and PBAC with an overall incidence of 3/38 (7-8%).…”

Section: Discussionmentioning

confidence: 82%

Clinical sequencing identifies potential actionable alterations in a high rate of urachal and primary bladder adenocarcinomas

Váradi

Nagy

Reis

et al. 2022

Preprint

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Administration of targeted therapies provides a promising treatment strategy for rare cancers such as urachal adenocarcinoma (UrC) or primary bladder adenocarcinoma (PBAC), however, the selection of appropriate drugs remains difficult. Therefore, in the present study, we aimed to establish a routine compatible methodological pipeline for the identification of the most important therapeutic targets and potentially effective drugs for UrC and PBAC. Next-generation sequencing using a 161 cancer driver gene panel was performed on 41 UrC and 13 PBAC samples. Clinically relevant alterations were filtered by four publicly available databases. Therapeutic interpretation has been performed by in silico evaluation of drug-gene interactions using an evidence-based decision support tool. After data processing, 45/54 samples (33 UrC and 12 PBAC) passed the quality control. The sequencing analyses revealed a total of 191 pathogenic SNVs in 68 genes. The most frequent gain-of-function mutations in UrC were found in KRAS (33%), MYC (15%), EGFR (9%) and ERBB2 (9%), while in PBAC KRAS (25%), MYC (25%), FLT3 (17%) and TERT (17%) were recurrently affected. The most frequently affected pathways in both tumour types were related to cell cycle regulation, DNA damage control and the MAPK/RAS pathway. Actionable mutations with at least one available, regulatory agency-approved drug could be identified for 31/33 (94%) of UrC and 8/12 (67%) of PBAC patients. In this study, we used a commercially available assay and developed a data processing pipeline for the detection and therapeutic interpretation of genetic alterations in two rare cancers. Our analyses revealed actionable mutations in a high rate of cases, including EGFR, BRCA, CCND1/2/3, ERBB2, METex14 suggesting a potentially feasible strategy for both UrC and PBAC treatment.

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“…Mutations in exon 14 are the most common MET mutations found in NSCLC patients ( 18 ). The majority of MET exon 14 mutations are point mutations, but indels, insertions, and deletions are also found ( 19 ).…”

Section: The Biological Features Of Lung Cancermentioning

confidence: 99%

Current treatments for non-small cell lung cancer

et al. 2022

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Despite improved methods of diagnosis and the development of different treatments, mortality from lung cancer remains surprisingly high. Non-small cell lung cancer (NSCLC) accounts for the large majority of lung cancer cases. Therefore, it is important to review current methods of diagnosis and treatments of NSCLC in the clinic and preclinic. In this review, we describe, as a guide for clinicians, current diagnostic methods and therapies (such as chemotherapy, chemoradiotherapy, targeted therapy, antiangiogenic therapy, immunotherapy, and combination therapy) for NSCLC.

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Lung Cancer with MET exon 14 Skipping Mutation: Genetic Feature, Current Treatments, and Future Challenges

Cited by 51 publications

References 89 publications

MET∆14 promotes a ligand-dependent, AKT-driven invasive growth

MET∆14 promotes a ligand-dependent, AKT-driven invasive growth

Clinical sequencing identifies potential actionable alterations in a high rate of urachal and primary bladder adenocarcinomas

Current treatments for non-small cell lung cancer

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