<i>MET</i> Exon 14 Skipping in Non-Small Cell Lung Cancer

Heist, Rebecca S.; Shim, Hyo Sup; Gingipally, Shalini; Mino‐Kenudson, Mari; Le, Long P.; Gainor, Justin F.; Zheng, Zongli; Aryee, Martin J.; Xia, Junfeng; Jia, Peilin; Jin, Hailing; Zhao, Zhongming; Pao, William; Engelman, Jeffrey A.; Iafrate, A. John

doi:10.1634/theoncologist.2015-0510

Cited by 95 publications

(71 citation statements)

References 27 publications

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“…Although the results are strongly limited in terms of generalizability by the small size of the patients' cohort (n=28), the MET exon 14 splicing alterations seem to occur in older adults (median age: 72.5 years) with a history of tobacco use (64% of cases) (33). Nevertheless, in the context of a small cohort of 54 never-smoker patients affected by lung cancers that were WT for other validated driver alterations, MET exon 14 skipping mutations were detected in 19% of the cases (31).…”

Section: Lung Cancermentioning

confidence: 93%

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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Section: Lung Cancermentioning

confidence: 93%

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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“…Disruption of the CBL binding site leads to prolonged half-life and increased transforming activity. Exon 14 skipping in the MET gene commonly occurs in lung cancers and also disrupts CBL recognition, thereby stabilizing MET (239,240). Another oncogenic form of MET that lacks the CBL binding site is TPR (translocated promoter region)-MET, which is generated through a chromosomal translocation that results in combining the dimerization domain of TPR (a scaffolding element of the nuclear pore complex) with the kinase domain of MET.…”

Section: Disruption Of One E3 Ligase With Multiple Functionally Relatmentioning

confidence: 99%

Degrons in cancer

et al. 2017

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Degrons are the elements that are used by E3 ubiquitin ligases to target proteins for degradation. Most degrons are short linear motifs embedded within the sequences of modular proteins. As regulatory sites for protein abundance, they are important for many different cellular processes, such as progression through the cell cycle and monitoring cellular hypoxia. Degrons enable the elimination of proteins that are no longer required, preventing their possible dysfunction. Although the human genome encodes~600 E3 ubiquitin ligases, only a fraction of these enzymes have well-defined target degrons. Thus, for most cellular proteins, the destruction mechanisms are poorly understood. This is important for many diseases, especially for cancer, a disease that involves the enhanced expression of oncogenes and the persistence of encoded oncoproteins coupled with reduced abundance of tumor suppressors. Lossof-function mutations occur in the degrons of several oncoproteins, such as the transcription factors MYC and NRF2, and in various mitogenic receptors, such as NOTCH1 and several receptor tyrosine kinases. Mutations eliminating the function of the b-catenin degron are found in many cancers and are considered one of the most abundant mutations driving carcinogenesis. In this Review, we describe the current knowledge of degrons in cancer and suggest that increased research on the "dark degrome" (unknown degron-E3 relationships) would enhance progress in cancer research.

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“…Importantly, these studies uncovered a novel and distinct mechanism of oncogenic RTK activation through altered RTK downregulation (27,28). The incidence of MET mutations in lung cancers is 3% in squamous cell lung cancers, 5.6% in NSCLC, and 8% in lung adenocarcinomas (29)(30)(31). The implications of MET JM domain mutations and receptor regulation on the clinical outcome of lung cancer patients have become evident in recent years (32)(33)(34)(35)(36)(37).…”

Section: Met Juxtamembrane and Sema Domain Mutationsmentioning

confidence: 99%

MET in human cancer: germline and somatic mutations

Tovar

Graveel

2017

Ann. Transl. Med.

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Since the initial discovery of missense MET mutations in hereditary papillary renal carcinoma (HPRC), activating MET mutations have been identified in a diverse range of human cancers. MET mutations have been identified in several functional domains including the kinase, juxtamembrane, and Sema domains. Studies of these mutations have been invaluable for our understanding of the tumor initiating activity of MET, receptor tyrosine kinase (RTK) recycling and regulation, and mechanisms of resistance to kinase inhibition. These studies also demonstrate that mutationally activated MET plays a significant role in a wide range of cancers and RTKs can promote tumor progression through diverse mechanisms. This review will cover the various MET mutations that have been identified, their mechanism of action, and the significant role that mutationally-activated MET plays in tumor initiation, progression, and therapeutic resistance.

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MET Exon 14 Skipping in Non-Small Cell Lung Cancer

Cited by 95 publications

References 27 publications

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

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

Degrons in cancer

MET in human cancer: germline and somatic mutations

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