Differential Response of MET inhibition by Glesatinib (MGCD265) and Sitravatinib (MGCD516) in Non‐small Cell Lung Cancer and Malignant Mesothelioma

Abstract

Aberrant activation of the receptor tyrosine kinase (RTK) MET is frequently involved in malignant transformation and inhibiting its activity in dependent cancers is associated with improved clinical outcomes. Glesatinib (MGCD265) and sitravatinib (MGCD516) are next generation MET RTK inhibitors (RTKIs) and while glesatinib also targets the AXL RTK, sitravatinib inhibits a closely related spectrum of RTKs. The efficacy of these compounds in MET‐dependent non‐small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM) cell lines that differed with respect to MET gene expression was evaluated. Both drugs inhibited cell growth and migratory activity with similar potency in NSCLC H1993 cells with clustered MET amplification and A459 cells with ‘wild type’ MET. Also, MPM cell lines H2373 and H2461 with elevated MET expression showed comparable levels of sensitivity to either drug. Kinomics analysis of the affected pathways suggested that both drugs acted similarly, yet distinct signaling was affected when different cell lines were tested. In particular, cellular pathways associated with transformation were inhibited whereas those promoting cell death were activated upon drug treatment. Furthermore, phosphorylation of RON, which interacts with MET, and the downstream signaling molecules AKT and p44/42MAPK were also inhibited in response to hepatocyte growth factor (HGF) stimulation. Importantly, in a pre‐clinical in vivo xenotransplant mouse model, both drugs caused significant tumor growth inhibition. Our data suggest that discerning the expression and activation status of MET and its associated signaling pathways may help guide treatment decisions concerning targeted therapies for NSCLC and MPM.Support or Funding InformationThe National Cancer Institute of the National Institutes of Health under award number P30CA033572 and Mirati Therapeutics.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.