Targeting the Met pathway in lung cancer

Abstract

Dysregulation of Met signaling has been implicated in the initiation, progression and metastasis of human cancers, and therefore represents an attractive target for anticancer drug development. Met is overexpressed in non-small-cell lung cancer and its lack of staining in normal lung tissue makes it an attractive target. To date, erlotinib and gefitinib have established themselves as first-line therapy for non-small-cell lung cancer patients whose tumors harbor an EGF receptor gene mutation, and hence, it is crucial that we identify mechanisms of resistance that could be targeted by novel agents, while keeping an acceptable toxicity profile at the same time; something very important when we develop these new drugs. Inhibitors of the Met pathway represent a therapeutic alternative in this setting. In this review, we discuss the early clinical studies reported using two Met inhibitors, a monoclonal antibody (MetMAb) and a small molecule tyrosine kinase inhibitor (MGCD265).

MiR-130a Overcomes Gefitinib Resistance by Targeting Met in Non-Small Cell Lung Cancer Cell Lines

“…Soon afterwards, more researchers reported that Met amplification and its phosphorylation are associated with both primary and acquired resistance to EGFR TKI therapies in NSCLC patients (Guo et al, 2008;Suda et al, 2010;Belalcazar et al, 2012). Together, these reports implicate Met as a potentially effective therapeutic target to reverse resistance to this important class of drugs in NSCLC.…”

MET Amplification Status in Therapy-Naïve Adeno- and Squamous Cell Carcinomas of the Lung

“…Binding of HGF to MET triggers receptor dimerization and transphosphorylation, which lead to conformational changes of the receptor with subsequent activation of the tyrosine kinase (TK). Activation of the TK domain in turn mediates downstream signaling via the PI3K/AKT, RAS-RAC/RHO, MAPK, and phospholipase C pathways (8,9). During embryogenesis, MET receptors are expressed on epithelial cells as well as on muscle precursor cells to mediate epithelial-to-mesenchymal transition which is essential for limb bud development (10).…”

“…In preclinical models, lung cancer cell lines with MET amplification were shown to be dependent on MET signaling for growth and survival (25). As a result, many new MET inhibition compounds (including antibody inhibition, small-molecule inhibitors, and others) have entered clinical trials (9). However, to date the frequency of MET amplification in NSCLC remains controversial and it ranges from 3% to 10%, depending on the detection technique, cutoff criteria, and selection of samples (15)(16)(17)(18)26).…”

Biochemical and pharmacological characterization of human c-Met neutralizing monoclonal antibody CE-355621

“…Clinical benefit was demonstrated in NSCLC patients with tumors expressing elevated levels of Met protein (≥ 50% tumor cells having 2-3+ IHC staining) who were treated with onartuzumab and erlotinib, and a durable complete response was observed in a metastatic gastric cancer patient with high MET polysomy and Met protein expression detected by immunohistochemistry who was treated with onartuzumab. [52][53][54][55] CE-355621 appears to exhibit superior binding and neutralizing activity for its target in biochemical assays compared with onartuzumab. The affinity of bivalent CE-355621 for native c-Met is ~56 pM and for recombinant c-Met ECD is ~200 pM; whereas, the affinity of monovalent 5D5 (onartuzumab) for c-Met is ~4 nM.…”