Synergism of FAK and ROS1 inhibitors in the treatment of <i>CDH1</i>-deficient cancers mediated by FAK-YAP signaling

Abstract

<i>CDH1</i> deficiency is common in diffuse gastric cancer and triple negative breast cancer patients, both of which still lack effective therapeutics. ROS1 inhibition results in synthetic lethality in <i>CDH1</i>-deficient cancers, but often leads to adaptive resistance. Here, we demonstrate that upregulation of the FAK activity accompanies the emergence of resistance to ROS1 inhibitor therapy in gastric and breast <i>CDH1</i>-deficient cancers. FAK inhibition, either by FAK inhibitors or by knocking down its expression, resulted in higher cytotoxicity potency of the ROS1 inhibitor in <i>CDH1</i>-deficient cancer cell lines. Co-treatment of mice with the FAK inhibitor and ROS1 inhibitors also showed synergistic effects against <i>CDH1</i>-deficient cancers. Mechanistically, ROS1 inhibitors induce the FAK-YAP-TRX signaling, decreasing oxidative stress-related DNA damage and consequently reducing their anti-cancer effects. The FAK inhibitor suppresses the aberrant FAK-YAP-TRX signaling, reinforcing ROS1 inhibitor's cytotoxicity towards cancer cells. These findings support the use of FAK and ROS1 inhibitors as a combination therapeutic strategy in <i>CDH1</i>-deficient triple negative breast cancer and diffuse gastric cancer patients.