Understanding and Targeting MET Signaling in Solid Tumors - Are We There Yet?

Ariyawutyakorn, Witthawat; Saichaemchan, Siriwimon; Varella‐Garcia, Marileila

doi:10.7150/jca.12663

Cited by 34 publications

(24 citation statements)

References 113 publications

(205 reference statements)

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“…Similarly to clear-cell RCC, MET mutations (and specifically in the exon 14) have not been identified in prostate cancer, while Met expression has been correlated with the castration-resistant tumor proliferation (75,76). Although pre-clinical and early phase trials suggested a potential activity of Met inhibitors in prostate cancer, phase III trials, such as the COMET-1, failed to demonstrate positive results (77).…”

Section: Other 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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Section: Other 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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“…A number of MET-targeted TKIs and therapeutic antibodies have entered clinical development, but so far, none have been approved as MET-targeting agents (9). TKIs generally have limited target specificity, which may lead to pleiotropic effects and unwanted toxicity.…”

Section: Introductionmentioning

confidence: 99%

Sym015: A Highly Efficacious Antibody Mixture against MET-Amplified Tumors

Poulsen

Grandal

Skartved

et al. 2017

Clinical Cancer Research

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Activation of the receptor tyrosine kinase MET is associated with poor clinical outcome in certain cancers. To target MET more effectively, we developed an antagonistic antibody mixture, Sym015, consisting of two humanized mAbs directed against nonoverlapping epitopes of MET. We screened a large panel of well-annotated human cancer cell lines and identified a subset with highly elevated MET expression. In particular, cell lines of lung cancer and gastric cancer origin demonstrated high MET expression and activation, and Sym015 triggered degradation of MET and significantly inhibited growth of these cell lines. Next, we tested Sym015 in patient- and cell line-derived xenograft models with high MET expression and/or exon 14 skipping alterations, and in models harboring amplification as a mechanism of resistance to EGFR-targeting agents. Sym015 effectively inhibited tumor growth in all these models and was superior to an analogue of emibetuzumab, a monoclonal IgG4 antibody against MET currently in clinical development. Sym015 also induced antibody-dependent cellular cytotoxicity (ADCC) , suggesting that secondary effector functions contribute to the efficacy of Sym015.Retrospectively, all responsive, high MET-expressing models were scored as highly-amplified by hybridization, pointing to amplification as a predictive biomarker for efficacy. Preclinical toxicology studies in monkeys showed that Sym015 was well tolerated, with a pharmacokinetic profile supporting administration of Sym015 every second or third week in humans. The preclinical efficacy and safety data provide a clear rationale for the ongoing clinical studies of Sym015 in patients with -amplified tumors..

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“…We found that activated EGFR, MET, AXL, EPHB1, and EPHB2 were basally detected in HCT116 cells (Figure A, left) and phosphorylated EGFR, MET, ERBB3, Insulin R, and IGF‐1R were basally detected in HT29 cells (Figure A, right). MET is known to be abnormally activated in many cancers, and its activation has been reported to contribute to tumour growth, proliferation, and survival . These patterns were further confirmed by western blot analysis.…”

Section: Discussionmentioning

confidence: 53%

“…MET is known to be abnormally activated in many cancers, and its activation has been reported to contribute to tumour growth, proliferation, and survival. 33,34 These patterns were further confirmed by western blot analysis. Interestingly, phosphorylated MET decreased by paroxetine treatment in both the cell lines, suggesting that MET could be a common target for paroxetine ( Figure 4B).…”

Section: Discussionmentioning

confidence: 55%

Anticancer activity of paroxetine in human colon cancer cells: Involvement of MET and ERBB3

Jang

Jung

et al. 2018

J Cellular Molecular Medi

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The concept of drug repositioning has recently received considerable attention in the field of oncology. In the present study, we propose that paroxetine can be used as a potent anticancer drug. Paroxetine, one of the selective serotonin reuptake inhibitors (SSRIs), has been widely prescribed for the treatment of depression and anxiety disorders. Recently, SSRIs have been reported to have anticancer activity in various types of cancer cells; however, the underlying mechanisms of their action are not yet known. In this study, we investigated the potential anticancer effect of paroxetine in human colorectal cancer cells, HCT116 and HT‐29. Treatment with paroxetine reduced cell viability, which was associated with marked increase in apoptosis, in both the cell lines. Also, paroxetine effectively inhibited colony formation and 3D spheroid formation. We speculated that the mode of action of paroxetine might be through the inhibition of two major receptor tyrosine kinases – MET and ERBB3 – leading to the suppression of AKT, ERK and p38 activation and induction of JNK and caspase‐3 pathways. Moreover, in vivo experiments revealed that treatment of athymic nude mice bearing HT‐29 cells with paroxetine remarkably suppressed tumour growth. In conclusion, paroxetine is a potential therapeutic option for patients with colorectal cancer.

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Understanding and Targeting MET Signaling in Solid Tumors - Are We There Yet?

Cited by 34 publications

References 113 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

Sym015: A Highly Efficacious Antibody Mixture against MET-Amplified Tumors

Anticancer activity of paroxetine in human colon cancer cells: Involvement of MET and ERBB3

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