Abstract LB-021: Focal adhesive kinase inhibitor IN10018 sensitizes KRAS mutant cancer and overcomes drug resistance of KRAS G12C inhibition

Abstract

Abstract KRAS mutation is found in around 20-30% of human cancer. Previously, lack of targeting therapy limited the treatment outcomes. Recently, KRAS G12C inhibitors like AMG510, MRTX849, and MRTX1257 were developed and exhibited promising therapeutic outcomes targeting the mutation. However, a considerable amount of cases showed less sensitivity, indicating either intrinsic or adaptive resistance mechanisms. Other reports and our own data exhibited that Focal Adhesive Kinase (FAK) inhibition showed good treatment effects to KRAS mutant cancer. Interestingly, TCGA data analysis reveal that FAK mRNA expression level is significantly higher in KRAS mutant tumors. Considering that FAK is one predominant target for cancer treatment resistance, we hypothesize that FAK is one of mediator leading to resistance mechanism of KRAS G12C inhibition. To explore our hypothesis, we employed high potent FAK inhibitor IN10018, which is being tested in phase I clinical trial for different cancer types. First, we found that IN10018 is active in a series of KRAS mutated cancer xenograft models. The compound sharply decreased the level of phosphoFAK Y397, a direct marker for FAK activity. Then we investigated whether combination of IN10018 with KRAS G12C inhibitors can show synergic effects in vitro and in vivo. IN10018 in combination with either AMG510 or MRTX1257 showed better effects in killing KRAS G12C cancer cells than each single treatment. More importantly a significant synergy between IN10018 with KRAS G12C inhibitors against KRAS mutated cancer cell lines was observed in vivo. Further evidence showed that KRAS G12C inhibition can significantly increase the expression of phosphoFAK Y397, suggesting a possible underlying mechanism of resistance to KRAS G12C inhibitors. IN10018 significantly decreased the upregulated FAK Y397 phosphorylation in the combination treatments, underlying the mechanism of synergy between the two inhibitors. Our results indicate that KRAS G12C cancer patients can be better treated by the combination of IN10018 with KRAS G12C inhibitor. Citation Format: Baoyuan Zhang, Yan Zhang, Jiangwei Zhang, Ping Liu, Bo Jiao, Zaiqi Wang, Ruibao Ren. Focal adhesive kinase inhibitor IN10018 sensitizes KRAS mutant cancer and overcomes drug resistance of KRAS G12C 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 LB-021.