Abstract #820: Combination studies of tyrosine kinase inhibitors (TKIs): Assessment of potential cytotoxic synergy of ARQ 197 with sorafenib or sunitinib

ARQ 197 is a novel, clinically well-tolerated orally available anti-cancer drug candidate shown to inhibit c-Met driven tumors in vitro and in vivo. To complement Phase I data showing clinical response as a single agent, we sought to explore the potential synergy of ARQ 197 with two marketed TKIs, sorafenib and sunitinib. A panel of 87 human cancer cell lines encompassing a spectrum of genotypes and tissue origins were surveyed in 72 h MTS cytotoxicity assays across a wide range of compound concentrations. Isobologram analyses categorized drug combinations as synergistic, additive, or antagonistic. The combination of ARQ 197 and sorafenib revealed synergistic cytotoxicity in NCI-H522 (NSCLC), MDA-MB-231 (breast), A375 (melanoma), NCI-H526 (SCLC), and in HeLa cervical carcinoma cell lines. Additivity was seen with the ARQ 197/sorafenib combination in the HCC1395 breast cancer line, the Colo205 and SW480 colon cancer lines, the Caki-1 (RCC) line, the squamous cell carcinoma A431 line, the NCI-H358 (NSCLC) cell line, and 3 hepatocellular carcinomas (JHH-4, PLC/PRF/5, SK-Hep-1). The remainder of the cell lines showed resistance (19 cell lines) to either ARQ 197, sorafenib or both agents, antagonism (14 cell lines) to the combination of ARQ 197 and sorafenib, or yielded equivocal data. In contrast to sorafenib, the combination of ARQ 197 and sunitinib showed no clear synergy with any of the 87 cell lines tested. Quite striking was the number of cell lines (46 in total) in which antagonism of ARQ 197 and sunitinib was evident. In summary, the combination of ARQ 197 and sorafenib revealed a number of tumor types in which the compounds were synergistic with respect to cytotoxicity. This data may be informative in the design of combination therapy regimens for ARQ 197. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 820.