Abstract 1958: Repotrectinib increases effectiveness of KRAS-G12C inhibitors in KRAS-G12C mutant cancer models via simultaneous SRC/FAK/JAK2 inhibition

KRAS is frequently mutated in multiple cancer types. Therapeutic targeting of KRAS has proven challenging until recent success of KRAS-G12C inhibitor AMG510 that demonstrated tumor regression in lung and colon cancer patients with a KRAS-G12C mutation. However, resistance via feedback reactivation or development of a bypass are expected to limit anti-tumor efficacy of KRAS-G12C inhibitors, favoring a combination approach. Adaptive upregulation of the PI3K/AKT signaling pathway has been recognized as a common resistance mechanism that promotes cancer cell survival and may temper efficacy of KRAS-G12C inhibitors. SRC/FAK signaling promotes tumor cell survival by activation of the PI3K/AKT survival pathway supporting concomitantly targeting SRC/FAK as a promising strategy to potentiate KRAS G12C inhibitors. In addition, oncogenic KRAS induces secretion of various cytokines and growth factors leading to modulation of the tumor microenvironment to promote tumor growth. Targeting the cytokine secretion pathway via JAK2/STAT3 modulation may be important to overcome the resistance to direct KRAS inhibition. Therefore, combinations of KRAS inhibitors with agents that target apoptotic processes and feedback reactivation may represent a promising therapeutic approach. Repotrectinib, a next generation ROS1/TRK/ALK inhibitor, also inhibits SRC/FAK/JAK2 at therapeutically relevant concentrations. Here, we present synergistic effects of repotrectinib in combination with a KRAS-G12C inhibitor in KRAS-G12C mutant cancer models via simultaneous inhibition of SRC/FAK/JAK2. Adding repotrectinib to AMG510 improves AMG510 effectiveness on KRAS-G12C mutant cancer cells with notably increased apoptosis. For example, repotrectinib (1 μM) shifted the antiproliferation IC50 of AMG510 from 213 nM to 3 nM in KRAS-G12C mutant H358 cells. Treatment of H358 cells with AMG510 alone (100 nM) or repotrectinib alone (1 µM) resulted in slight increases in cleaved PARP and caspase-3 proteins, whereas larger increases were observed with the combination. Although high levels of phosphorylated ERK, AKT, STAT3 and FAK were detected in H358 cells, AMG510 (100 nM) was only able to partially modulate phospho-ERK (pERK) with no modulation on pAKT, pSTAT3 and pFAK and repotrectinib (1 μM) suppressed pSTAT3 and pFAK with minimum modulation on pERK and pAKT. The combination in H358 cells results in stronger suppression of pERK and pAKT than either single agent alone, which is consistent with the observed increase in activation of apoptosis. Additional combination data in KRAS-G12C mutant cancer models will be presented. Overall, these studies warrant further clinical investigation on the combination of KRAS-G12C inhibitors with repotrectinib in patients with KRAS-G12C mutation for potential response and duration improvement of current investigational KRAS-G12C inhibitors. Citation Format: J. Jean Cui, Dayong Zhai, Wei Deng, Laura Rodon, Nathan Lee, Brion Murray. Repotrectinib increases effectiveness of KRAS-G12C inhibitors in KRAS-G12C mutant cancer models via simultaneous SRC/FAK/JAK2 inhibition [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1958.