MET 14 Deletion in Sarcomatoid Non-Small-Cell Lung Cancer Detected by Next-Generation Sequencing and Successfully Treated with a MET Inhibitor

The mesenchymal epithelial transition factor receptor (MET) is a potential therapeutic target in a number of cancers, including non-small cell lung cancer (NSCLC). In NSCLC, MET pathway activation is thought to occur via a diverse set of mechanisms that influence properties affecting cancer cell survival, growth, and invasiveness. Preclinical and clinical evidence suggest a role for MET activation as both a primary oncogenic driver in subsets of lung cancer, and as a secondary driver of acquired resistance to targeted therapy in other genomic subsets. In this review, we explore the biology and clinical significance behind MET exon 14 (METex14) alterations and MET amplification in NSCLC, the role of MET amplification in the setting of acquired resistance to EGFR tyrosine kinase inhibitor therapy in EGFR-mutant NSCLC, and the history of MET pathway inhibitor drug development in NSCLC, highlighting current strategies that enrich for biomarkers that are likely to be predictive of response. While previous trials that focused on MET pathway-directed targeted therapy in unselected or MET overexpressing NSCLC yielded largely negative results, more recent investigations focusing on METex14 alterations and MET amplification have been notable for meaningful clinical responses to MET inhibitor therapy in a substantial proportion of patients.

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“…29 Subsequent case reports have confirmed these observations using different MET TKIs and in all NSCLC histologies. 30, 37–40 …”

Section: Met As a Primary Driver In Nsclcmentioning

confidence: 99%

Targeting MET in Lung Cancer: Will Expectations Finally Be MET?

Drilon

Cappuzzo

et al. 2017

Journal of Thoracic Oncology

317

277

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“…Importantly, in two separate case reports, NGS detected the presence of a MET exon 14 splice-site mutation in NSCLC tumor tissue, and in each case report, the patient was treated with the MET inhibitor crizotinib and showed a partial response or a significant decrease in tumor size [124, 125]. In another study, tumor samples from 178 patients with advanced NSCLC were sequenced using hybrid capture-based NGS.…”

Section: Genetic Analysismentioning

confidence: 99%

Cell-free DNA and next-generation sequencing in the service of personalized medicine for lung cancer

et al. 2016

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Personalized medicine has emerged as the future of cancer care to ensure that patients receive individualized treatment specific to their needs. In order to provide such care, molecular techniques that enable oncologists to diagnose, treat, and monitor tumors are necessary. In the field of lung cancer, cell free DNA (cfDNA) shows great potential as a less invasive liquid biopsy technique, and next-generation sequencing (NGS) is a promising tool for analysis of tumor mutations. In this review, we outline the evolution of cfDNA and NGS and discuss the progress of using them in a clinical setting for patients with lung cancer. We also present an analysis of the role of cfDNA as a liquid biopsy technique and NGS as an analytical tool in studying EGFR and MET, two frequently mutated genes in lung cancer. Ultimately, we hope that using cfDNA and NGS for cancer diagnosis and treatment will become standard for patients with lung cancer and across the field of oncology.

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“…In comparison with the relative low frequency of detection observed in "classic" lung cancer (numerically comparable to the ALK rearrangement frequency), a strikingly high rate of MET exon 14 skipping mutations, mutually exclusive with other validated driver alterations, was most recently detected in pulmonary sarcomatoid carcinoma (PSC) (22%) (35,52,53). Moreover, an impressive clinico-radiological response was described in a woman affected by an advanced chemotherapy resistant PSC harboring a MET exon 14 skipping mutation, providing further strong proof of the clinical relevance of the findings (35).…”

Section: Sarcomatoid Tumorsmentioning

confidence: 99%

MET exon 14 juxtamembrane splicing mutations: clinical and therapeutical perspectives for cancer therapy

Pilotto¹,

Gkountakos²,

Carbognin³

et al. 2017

Ann. Transl. Med.

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Abstract:The MET proto-oncogene plays crucial roles in cell growth and proliferation, survival and apoptosis, epithelial-mesenchymal transition (EMT) and invasion, potentially conditioning the development and progression of the carcinogenesis process. The MET-associated aberrant signaling could be triggered by a variety of mechanisms, such as mutations, gene amplification, increased gene copy number and Met/HGF protein expression. Among the various MET alterations, MET exon 14 splicing abnormalities, causing the loss of the Met juxtamembrane (JM) domain, recently emerged as a new potential oncogenic driver and have been identified and validated across different cancer and histology subtypes. Moreover, this aberration was found to be mutually exclusive with other recognized drivers, thus strongly nominating its potential oncogenic role. Recently, the clinical activity of anti-Met-targeted therapy was demonstrated particularly in patients harboring MET exon 14 skipping lung cancer, resulting in a renewed enthusiasm to further test MET precision therapy in prospective trials. In this review, the key preclinical and clinical data regarding MET exon 14 skipping splicing variants as an actionable genomic aberration in cancer are described, and the perspectives deriving from the validation of such alteration as a potential target, which may further allow driving the therapeutic approach in this molecularly selected patients' subgroup, are explored.

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MET 14 Deletion in Sarcomatoid Non-Small-Cell Lung Cancer Detected by Next-Generation Sequencing and Successfully Treated with a MET Inhibitor

Cited by 41 publications

References 5 publications

Targeting MET in Lung Cancer: Will Expectations Finally Be MET?

Targeting MET in Lung Cancer: Will Expectations Finally Be MET?

Cell-free DNA and next-generation sequencing in the service of personalized medicine for lung cancer

MET exon 14 juxtamembrane splicing mutations: clinical and therapeutical perspectives for cancer therapy

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