ERK5 suppression overcomes FAK inhibitor resistance in mutant KRAS-driven non-small cell lung cancer
- EMBO Mol Med. 2024 Oct;16(10):2402-2426. doi: 10.1038/s44321-024-00138-7.
- 1. Institute of Pharmacology, University of Bern, 3010, Bern, Switzerland.
- 2. Department of Neuroscience, Biomedicine and Movement, University of Verona, 37134, Verona, Italy.
- 3. Department of Cell Physiology and Metabolism, University of Geneva, 1211, Geneva, Switzerland.
- 4. Diabetes Center of the Faculty of Medicine, University of Geneva, 1211, Geneva, Switzerland.
- 5. Institute of Pharmacology, University of Bern, 3010, Bern, Switzerland. [email protected].
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.