Abstract 4808: Combinations of imatinib mesylate with AKT inhibitor (miransertib, ARQ 751) or FGFR inhibitor (derazantinib) show synergy in GIST cell lines and preclinical models

The majority of gastrointestinal stromal tumors (GIST) harbor oncogenic mutations in the receptor tyrosine kinase KIT or platelet-derived growth factor receptor alpha (PDGFRA). Small molecule kinase inhibitors such as imatinib mesylate (IM) have significantly improved the clinical management of GIST by targeting these mutant receptors. Despite strong overall response rates to IM, disease progression generally occurs with time. Inhibiting targets other than, or in addition to, KIT/PDGFRA may provide additional therapeutic benefit in GIST patients. Both AKT and FGFR signaling have recently been reported to be resistance mechanisms associated with survival of IM-resistant GIST cell lines and tumors. In this study, we performed in vitro and in vivo experiments to assess the potential benefit of combining IM with the ArQule AKT inhibitors Miransertib (ARQ 092) and ARQ 751 and the FGFR inhibitor, Derazantinib (ARQ 087). To evaluate in vitro drug sensitivity, a panel of IM-sensitive (GIST-T1, GIST882) and resistant GIST cell lines (GIST-T1/829, GIST430) were subjected to drug treatment for 72 hours before measuring viability with the Cell Titer Blue Viability Assay. Synergy between IM and Miransertib, ARQ 751 and Derazantinib was quantified using the Chou-Talalay algorithm to calculate CI values. CI values Citation Format: Marya Kozinova, Shalina Joshi, Karthik Devarajan, Phillip Zook, Jimson W. D9Souza, Jeffrey M. Farma, Nestor Esnaola, Reza Foroughi, Yi Yu, Brian Schwartz, Terence Hall, Margaret von Mehren, Lori A. Rink. Combinations of imatinib mesylate with AKT inhibitor (miransertib, ARQ 751) or FGFR inhibitor (derazantinib) show synergy in GIST cell lines and preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4808.