Abstract 1639: The novel c-MET inhibitor, ARQ 197, shows additive growrh-inhibitory effect with erlotinib through enhanced degradation of c-MET protein via ubiquitin/proteasome pathway

Abstract

Background c-MET, a receptor of hepatocyte growth factor (HGF), is known to be overexpressed in a variety of human cancers. Recently several c-MET inhibitors are being developed as cancer chemotherapy against this compelling molecular target. ARQ 197 is a new small molecule c-MET inhibitor. Since ARQ 197 shows efficient anti-cancer activity without many severe adverse events in Phase I clinical trials, it is expected to be a useful anticancer agent for clinical treatment. This drug is known to bind to c-MET at neighbor area of its ATP binding site and it does not work as an ATP mimic. In this study, we investigated the molecular mechanism of inhibitory effect on c-MET by ARQ 197 in a non-small cell lung cancer cell (NSCLC) line. Materials and Method We established a c-MET-overexpressed NSCLC line, PC-9/MET, by long term exposure of PC-9 cells to EGFR-tyrosine kinase inhibitor. The cytotoxicity of ARQ 197 was measured by MTT assay. The expression of c-MET protein and mRNA were detected by Western blotting analysis and real time RT-PCR method, respectively. In a c-MET degradation analysis, bortezomib was used for inhibition of proteasome. Results ARQ 197 is equally cytotoxic to parental PC-9 and EGFRTKI-resistant PC-9/MET cell line with GI50 values around 200 nM (?). ARQ 197 showed an additive growth- inhibitory effect with erlotinib in PC-9/MET cells as assessed by an Isobologram analysis. In ARQ 197-treated PC-9/MET cells, a clear decrease of phospho c-MET protein as well as phospho AKT and ERK proteins was observed, however, ARQ 197 also induced a down-regulation of c-MET protein in the cells without any effect on c-MET mRNA level. This ARQ 197 induced degradation was reversed by a concomitant treatment with a proteasome inhibitor, bortezomib in the cells. However, bortezomib did not affect cytotoxicity of ARQ 197 in the same cells. Conclusion These data suggest that ARQ 197 may inhibit c-MET through downregulation of this protein in addition to inhibition of its kinase activity. Furthermore, it may enhance c-MET degradation by the ubiquitin/proteasome pathway. These c-MET inhibitory activities by ARQ 197 should be important for the additive combined effect with erlotinib in PC-9/MET cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1639.

Tumor and circulating biomarkers in patients with second-line hepatocellular carcinoma from the randomized phase II study with tivantinib

“…Tivantinib is an oral, ATP-independent inhibitor of MET, binding to its inactive form [ 16 , 17 ]; its anti-MET effect was confirmed by several groups, though some also suggested additional targets [ 18 - 20 ], including a weak non-specific anti-tubulin activity [ 21 - 23 ]. However, neurotoxicity, a hallmark of tubulin inhibitors, has not been reported in over 2000 patients treated with tivantinib to date, even at doses much higher than the therapeutic one [ 8 , 24 - 28 ].…”

Tivantinib in MET-high hepatocellular carcinoma patients and the ongoing Phase III clinical trial

“…Although details on the mechanism of action of tivantinib have been questioned in works led by Basilico and Katayama, hypothesizing a tubulin-related cytotoxic activity [22,23], with the former stating that tivantinib does not inhibit MET because it has activity in MET-low cells [22], three other independent groups recently confirmed the inhibitory activity of tivantinib on MET, adding involvement of Cyclin B1, proteasome and GSK3-a as additional targets of tivantinib [24][25][26][27]. Furthermore, paired tumor biopsies taken in patients before and after treatment with tivantinib showed inhibition of MET [28].…”

c-Met: A Potential Target for Current Non-Small-Cell Lung Cancer Therapeutics

“…Tivantinib has also been observed to induce apoptosis in c-Met activated cells by the ubiquitin/ proteosome pathway in vitro [34]. In addition to its activity against cMet, recent studies have indicated that tivantinib may exhibit anticancer inhibitory effects due to disruption of microtubule formation [35].…”