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

Abstract

Abstract 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 <1 are considered synergistic. The 3:1 molar ratio of the three tested combinations demonstrated synergistic CI values in all four GIST lines. Immunoblot assays confirmed that drugs inhibited their intended targets in each cell line following six-hour drug treatment. Interestingly, a significant decrease in the activation of a downstream signaling protein, p-S6, was observed in the AKTi+ IM -treated cells compared to cells treated with single agents. In vivo studies evaluating Miransertib, ARQ 751 and Derazantinib as monotherapies and in combination with IM were performed using GIST-T1 and GIST430 xenograft models, as well, as an IM-resistant, KIT exon 9-mutated GIST PDX model. In both IM-resistant GIST models, all three monotherapies (Miransertib, ARQ 751, Derazantinib) significantly inhibited tumor growth as compared to IM alone. In addition, combination therapy, with both AKTi and FGFRi, provided significantly greater efficacy in both IM-sensitive and resistant xenograft models of GIST. Together, these studies demonstrate that IM in combination with the novel ArQule AKT inhibitors (Miransertib and ARQ 751) and FGFR inhibitor (Derazantinib) provide significantly improved efficacy compared to monotherapy in the tested models. These results provide justification for development of translational trials evaluating these combinations in GIST patients. Citation Format: Marya Kozinova, Shalina Joshi, Karthik Devarajan, Phillip Zook, Jimson W. D'Souza, 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.