Abstract 5821: Synergism of FAK and ROS1 inhibitors in the treatment of CDH1-deficient cancers mediated by FAK-YAP-TRX signaling

Abstract

CDH1 deficiency is common in triple negative breast cancer and diffuse gastric cancer patients, both of which lack effective therapeutics. Although inhibiting ROS1 function results in synthetic lethality in CDH1-deficient cancers, adaptive resistance limits their potential clinical benefits. Hyperactive focal adhesion kinase (FAK) signaling contributes to adaptive drug resistance, and FAK inhibitors are partially effective against CDH1–deficient cancers. Thus, co-treatment with ROS1 and FAK inhibitors may provide stronger anti-cancer effects by targeting CDH1 deficiency and potentially overcome drug resistance. Here, we evaluated the effects and mechanisms of combined treatment with FAK inhibitor IN10018 and ROS1 inhibitors. Cell-based assays and in vivo animal experiments revealed that FAK and ROS1 inhibitor combination treatment showed stronger anti-cancer effects than either monotherapy. ROS1 inhibitors induced FAK-YAP-TRX signaling, decreasing oxidative stress–related DNA damage, and consequently reducing its anti-cancer effects. However, the combination treatment suppressed the aberrant FAK-YAP-TRX signaling, reinforcing the cytotoxicity of ROS1 inhibitor towards cancer cells. This mechanism of action was confirmed by inhibiting the activity of FAK-YAP-TRX downstream signaling molecules and by pretreatment with oxidative stress scavengers. These findings support the co-administration of FAK and ROS1 inhibitors as a therapeutic strategy in CDH1-deficient triple negative breast cancer and diffuse gastric cancer patients and support further clinical testing of this combination regimen. Citation Format: Jiaming Gao, Yunying Yao, Zaiqi Wang, Baoyuan Zhang, Ruibao Ren. Synergism of FAK and ROS1 inhibitors in the treatment of CDH1-deficient cancers mediated by FAK-YAP-TRX signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5821.