ERK5 suppression overcomes FAK inhibitor resistance in mutant KRAS-driven non-small cell lung cancer

Mutated KRAS serves as the oncogenic driver in 30% of non-small cell lung cancers (NSCLCs) and is associated with metastatic and therapy-resistant tumors. Focal Adhesion Kinase (FAK) acts as a mediator in sustaining KRAS-driven lung tumors, and although FAK inhibitors are currently undergoing clinical development, clinical data indicated that their efficacy in producing long-term anti-tumor responses is limited. Here we revealed two FAK interactors, extracellular-signal-regulated kinase 5 (ERK5) and cyclin-dependent kinase 5 (CDK5), as key players underlying FAK-mediated maintenance of KRAS mutant NSCLC. Inhibition of ERK5 and CDK5 synergistically suppressed FAK function, decreased proliferation and induced apoptosis owing to exacerbated ROS-induced DNA damage. Accordingly, concomitant pharmacological inhibition of ERK5 and CDK5 in a mouse model of KrasG12D-driven lung adenocarcinoma suppressed tumor progression and promoted cancer cell death. Cancer cells resistant to FAK inhibitors showed enhanced ERK5-FAK signaling dampening DNA damage. Notably, ERK5 inhibition prevented the development of resistance to FAK inhibitors, significantly enhancing the efficacy of anti-tumor responses. Therefore, we propose ERK5 inhibition as a potential co-targeting strategy to counteract FAK inhibitor resistance in NSCLC.The inhibition of ERK5 is a potential complementary strategy for countering FAK inhibitor resistance in patients with lung cancer harboring KRAS mutations.ERK and CDK5 work synergistically to enhance FAK function.Inhibition of ERK5/CDK5 or FAK induces cell death in NSCLC cells by increasing intracellular reactive oxygen species levels, which leads to DNA damage.Cancer cells resistant to FAK inhibitors exhibit upregulation of ERK5.Inhibiting ERK5 prevents the development of resistance to FAK inhibitors.The inhibition of ERK5 is a potential complementary strategy for countering FAK inhibitor resistance in patients with lung cancer harboring KRAS mutations.