Retrospective review of MET gene mutations

Zenali, Maryam; deKay, James; Liu, Zesheng; Hamilton, Stanley R.; Zuo, Zhuang; Lu, Xinyan; Bakkar, Rania; Mills, Gordon B.; Broaddus, Russell R.

doi:10.18632/oncoscience.161

Cited by 30 publications

(25 citation statements)

References 19 publications

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“…N375S variant frequently occurs in Asians and its biological role is unclear. In preclinical studies of lung cancer, the loss of binding affinity of c‐MET to HGF by N375S variant was analyzed in silico and they showed N375S variant conferred resistance to SU11274, c‐MET inhibitor . However, our results suggested that SNU‐638 with the N375S variant was more sensitive to c‐MET inhibitors than the other cell lines which did not have that variant (Fig.…”

Section: Discussionmentioning

confidence: 78%

Forty‐nine gastric cancer cell lines with integrative genomic profiling for development of c‐MET inhibitor

Kim

Kang

Kwon

et al. 2018

Intl Journal of Cancer

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Receptor tyrosine kinase MET (c-MET) has received considerable attention as a potential target for gastric cancer (GC) therapy and a number of c-MET inhibitors have been developed. For successful drug development, proper preclinical studies especially using patient derived cancer cell lines are very important. We profiled MET and MET-related characteristics in 49 GC cell lines to utilize them as models in preclinical studies of GC. Forty-nine cell lines were analyzed for genetic, biological, and molecular status to characterize MET and MET-related molecules. Four c-MET inhibitors were tested to elucidate the dependency on MET pathway in the 49 GC cell lines. Six of 49 cell lines were MET amplified with overexpression of c-MET and p-MET. The variants of MET were not associated with c-MET expression or amplification. Hs746T showed an exon 14 deletion in conjunction with MET amplification. The cell lines were divided into 6 MET amplified, 2 c-MET overexpressed, 2 hepatocyte growth factor (HGF) overexpressed, and 39 MET-negative subgroups. Except tivantinib, the c-MET inhibitors showed higher inhibition (%) in MET amplified than in MET nonamplified cell lines that MET amplified cell lines showed MET pathway dependency. However, the c-MET overexpressed and HGF overexpressed cell lines showed moderate dependency on MET pathway. Well-characterized cell lines are very important in studying drug development. Our 49 GC cell lines had various characteristics of MET and MET-related molecules and MET pathway dependency. These provide a promising platform for development of various RTK inhibitors including c-MET inhibitors.

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Section: Discussionmentioning

confidence: 78%

Forty‐nine gastric cancer cell lines with integrative genomic profiling for development of c‐MET inhibitor

Kim

Kang

Kwon

et al. 2018

Intl Journal of Cancer

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“…34 High c-MET expression or highly activated c-MET has also been reported in many types of tumors including CRC as c-MET is a proto-oncogene that is crucial for cancer progression. 35 To investigate any mechanistic or functional link between BRCA2 mutations and c-MET overexpression we used siRNA knockdown to effectively abrogate BRCA2. We hypothesized that BRCA2 deficiency would lead to increased double-strand DNA breaks in dividing cells or DNA damage exposed cells.…”

Section: Discussionmentioning

confidence: 99%

Preclinical rationale for combination of crizotinib with mitomycin C for the treatment of advanced colorectal cancer

Lev

Deihimi

Shagisultanova

et al. 2017

Cancer Biology & Therapy

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Colorectal cancer (CRC) is a leading cause of cancer-related deaths in the United States. We analyzed 26 MSI-High and 558 non-MSI-High CRC tumors. BRCA2 mutations were highly enriched (50%) in MSI-High CRC. Immunohistochemistry showed that BRCA2-mutated MSI-High CRC had high c-MET (64%) expression compared with BRCA-WT (17%). We hypothesized a mechanistic link between BRCA2-deficiency and c-MET overexpression and synergistic interaction between drugs that treat BRCA-deficient tumors (mitomycin C (MMC) or PARP inhibitors) and c-MET inhibitors (crizotinib). We tested CRC cell lines for sensitivity to MMC plus crizotinib or other drug combinations including PARP-inhibitors. Combined treatment of tumor cells with crizotinib and MMC led to increased apoptosis as compared with each drug alone. Additionally, combination treatment with increasing concentrations of both drugs demonstrated a synergistic anti-cancer effect (CI = 0.006-0.74). However, we found no evidence for c-MET upregulation upon effective BRCA2 knockdown in tumor cells -/+DNA damage. Although we found no mechanistic link between BRCA2 deficiency and c-MET overexpression, c-MET is frequently overexpressed in CRC and BRCA2 is mutated especially in MSI-H CRC. The combination of crizotinib with MMC appeared synergistic regardless of MSI or BRCA2 status. Using an in-vivo CRC xenograft model we found reduced tumor growth with combined crizotinib and MMC therapy (p = 0.0088). Our preclinical results support clinical testing of the combination of MMC and crizotinib in advanced CRC. Targeting cell survival mediated by c-MET in combination with targeting DNA repair may be a reasonable strategy for therapy development in CRC or other cancers.

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“…MET alterations (mainly involving overexpression) have been described in numerous human tumors, and they are often associated with a poor outcome (Scagliotti G, Novello, & von Pawel, ). Activating point mutations have been reported in sporadic and inherited forms of renal carcinoma, hepatocellular carcinoma, and several other cancer types (Ma et al., ; Schmidt et al., ; Zenali et al., ). A remarkably high incidence of somatic MET mutations was found in a series of 23 metastatic lesions arising from unknown primaries (Stella et al., ).…”

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confidence: 99%

Whole exome sequencing identifies a germline MET mutation in two siblings with hereditary wild-type RET medullary thyroid cancer

et al. 2017

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Whole exome sequencing (WES) was used to investigate two Italian siblings with wild-type RET genotype, who developed medullary thyroid cancers (MTCs) and, later, primary prostate and breast cancers, respectively. The proband's MTC harbored a p.Met918Thr RET mutation; his sister's MTC was RET/RAS wild-type. Both siblings had a germline mutation (p.Arg417Gln) in the extracellular Sema domain of the proto-oncogene MET. Experiments involving ectopic expression of MET p.Arg417Gln in MET-negative T47D breast cancer cells documented the mutant receptor's functionality and its ability to enhance cell migration and invasion. Our findings highlight a possible link between MET germline mutations and MTCs and suggest that MET p. Arg417Gln may promote an invasive malignant phenotype. The possibility that MTC can be driven/co-driven by a MET mutation has potential management implications, since the tyrosine-kinase inhibitor cabozantinib-approved for treating advanced MTCs-is a specific MET inhibitor.

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Retrospective review of MET gene mutations

Cited by 30 publications

References 19 publications

Forty‐nine gastric cancer cell lines with integrative genomic profiling for development of c‐MET inhibitor

Forty‐nine gastric cancer cell lines with integrative genomic profiling for development of c‐MET inhibitor

Preclinical rationale for combination of crizotinib with mitomycin C for the treatment of advanced colorectal cancer

Whole exome sequencing identifies a germline MET mutation in two siblings with hereditary wild-type RET medullary thyroid cancer

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