The Met receptor tyrosine kinase: A key player in oncogenesis and drug resistance

Maroun, Christiane R.; Rowlands, Tracey

doi:10.1016/j.pharmthera.2013.12.014

Cited by 184 publications

(181 citation statements)

References 223 publications

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“…The same rearrangement has since been identified in precursor lesions of gastric cancer, suggesting that it can pre-dispose to the development of gastric carcinomas [46]. Unlike the majority of oncogenes, mutations within the kinase domain of cMET are not frequent, although mutations have been found outside of the kinase domain (reviewed in [47]). Amplification of the cMET gene, or polysomy (of chromosome 7) is detected in a number of cancer types, and has been correlated with poor prognosis, high protein expression, and ligand-independent activation of Met (reviewed in [47]).…”

Section: Mis-regulation Mechanisms Of Hgf/cmetmentioning

confidence: 90%

“…Unlike the majority of oncogenes, mutations within the kinase domain of cMET are not frequent, although mutations have been found outside of the kinase domain (reviewed in [47]). Amplification of the cMET gene, or polysomy (of chromosome 7) is detected in a number of cancer types, and has been correlated with poor prognosis, high protein expression, and ligand-independent activation of Met (reviewed in [47]). As yet, there is no clinically validated method for defining cMET amplification, and thus the actual rate of amplification in tumour samples varies significantly between studies.…”

Section: Mis-regulation Mechanisms Of Hgf/cmetmentioning

confidence: 99%

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The Therapeutic Potential of Targeting the HGF/cMET Axis in Ovarian Cancer

Moran-Jones

2016

Mol Diagn Ther

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Survival rates for ovarian cancer have remained relatively stable for the past two decades, despite advances in surgical techniques and cytotoxic chemotherapeutics, indicating a requirement for better therapies. One pathway currently proposed for targeting is the HGF/cMET pathway. Up-regulated in a number of tumour types, cMET is a tyrosine kinase receptor expressed on epithelial cells. In ovarian cancer, it has been identified as highly expressed in the four major subtypes, with expression estimates ranging from 11-68% of cases. HGF, the only known ligand for cMET, is found at high levels in both serum and ascites in women with ovarian cancer, and proposed to induce both migration and metastasis. However, clinically validated biomarkers are not yet available for either HGF or cMET, preventing a clear understanding of the true rate of over-expression, or its correlation with prognosis.

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Section: Mis-regulation Mechanisms Of Hgf/cmetmentioning

confidence: 90%

Section: Mis-regulation Mechanisms Of Hgf/cmetmentioning

confidence: 99%

The Therapeutic Potential of Targeting the HGF/cMET Axis in Ovarian Cancer

Moran-Jones

2016

Mol Diagn Ther

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“…The MET-associated aberrant signaling could be triggered by a variety of mechanisms, such as mutations, gene amplification and high gene copy number, increased Met/HGF protein expression and by the crosstalk with other dysregulated pathways affecting Met activation (7).…”

Section: Introductionmentioning

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, which belongs to the MET/RON family, is a protooncogene located on chromosome 7q31.2 that encodes for a receptor tyrosine kinase (RTK) (16,17). The binding of HGF to the MET receptor favors its dimerization and its autophosphorylation on two tyrosine residues in its catalytic domain, Y1234 and Y1235.…”

Section: The Met Oncogenementioning

confidence: 99%

“…Physiologically, the binding of HGF to MET induces its activation, driving a complex biologic program of invasive growth from the promotion of cell proliferation and cell invasion, and protection from apoptosis (16). METdriven invasive growth is part of a physiological program that occurs during embryonic development and during adulthood within the context of tissue regeneration.…”

Section: Biochemical Mechanisms Permitting Met To Serve As a Key Bypamentioning

confidence: 99%