In our study, we used trebananib, an angiopoietin 1/2 inhibitor and a novel small molecule MET kinase inhibitor in patient derived xenograft (PDX) models of ccRCC.
Combination strategies of VEGF and MET inhibitors could lead to sustained and deep responses even in non-MET driven RCC by inhibiting pathways of VEGF resistance.
Fishing wild-type sparing inhibitors of proto-oncogene c-met variants in renal cell carcinoma from a curated tyrosine kinase inhibitor pool using analog-sensitive kinase technology.
Likewise, papillary RCC has also been studied at the molecular level, which has shown a high level of mutations in the MET gene; early clinical data suggest the utility of MET targeted therapy.
C-Met protein levels were increased in 8 of 10 RCC tissue samples compared with their adjacent normal tissue and c-Met expression levels were positively associated with a high nuclear grade (P = 0.008) and pT stage (P = 0.002).
For this purpose, tumor samples were analyzed for c-MET expression by immunohistochemistry (IHC), for c-MET copy number alterations by fluorescence in situ hybridization (FISH), and for c-MET mutations by next generation sequencing (NGS) in a retrospective cohort of 90 primary ccRCC of patients with metastases treated by first-line sunitinib.
Mechanistic, preclinical, and early clinical data highlight c-Met / hepatocyte growth factor receptor as a promising target for RCC therapeutic agents.We have examined MET expression, frequency of MET gene copy gains and MET gene mutation in a large, hospital-based series of renal cell carcinomas with long-term follow-up information.Out of a total of 572 clear-cell RCC, only 17% were negative forMET expression whereas 32% showed high protein levels.
Renal cell carcinoma (RCC) is a metabolic disease, being characterized by the dysregulation of metabolic pathways involved in oxygen sensing (VHL/HIF pathway alterations and the subsequent up-regulation of HIF-responsive genes such as VEGF, PDGF, EGF, and glucose transporters GLUT1 and GLUT4, which justify the RCC reliance on aerobic glycolysis), energy sensing (fumarate hydratase-deficient, succinate dehydrogenase-deficient RCC, mutations of HGF/MET pathway resulting in the metabolic Warburg shift marked by RCC increased dependence on aerobic glycolysis and the pentose phosphate shunt, augmented lipogenesis, and reduced AMPK and Krebs cycle activity) and/or nutrient sensing cascade (deregulation of AMPK-TSC1/2-mTOR and PI3K-Akt-mTOR pathways).
The exonic MET variant rs11762213 is an independent predictor of adverse CSS and TTR in ccRCC and should be integrated into clinical practice for prognostic stratification.
CTC FISH demonstrated that MET amplification in both gastric and colorectal cancer patients and trisomy 7 with gain of MET gene copies in the RCC patient.
If these results are further validated in a similar population, they could be incorporated into future prognostic instruments, potentially aiding the design of adjuvant clinical trials of MET inhibitors and management of renal-cell carcinoma.
Subsequent sequence analysis revealed a heterozygous R988C mutation of the MET gene and a VHL deletion in both the primary tumor and the tumor-derived ccRCC cell line.
Investigation of rare familial forms of renal cell carcinoma (RCC) has led to the identification of genes such as VHL and MET that are also implicated in the pathogenesis of sporadic RCC.
If these results are further validated in a similar population, they could be incorporated into future prognostic instruments, potentially aiding the design of adjuvant clinical trials of MET inhibitors and management of renal-cell carcinoma.
Germline mutations in the MET and fumarate hydratase (FH) genes lead to the development of type 1 and type 2 papillary RCCs, respectively, and such mutations of either the TSC1 or TSC2 gene increase the risk of RCC.
Presence of phosphorylated hepatocyte growth factor receptor/c-Met is associated with tumor progression and survival in patients with conventional renal cell carcinoma.