FAK-targeting PROTAC demonstrates enhanced antitumor activity against KRAS mutant non-small cell lung cancer

Abstract
Focal adhesion kinase (FAK) has emerged as a promising therapeutic target for KRAS-mutant non-small cell lung cancer (NSCLC). However, phase II clinical trials of the FAK inhibitor Defactinib have demonstrated only limited antitumor effects. To overcome this limitation, we present the use of a FAK-targeting proteolysis-targeting chimera (D-PROTAC) as a potential treatment for KRAS-mutant NSCLC. Our studies show that D-PROTAC effectively induces FAK protein degradation through the ubiquitin-proteasome pathway in KRAS-mutant A427 NSCLC cells, achieving over 90% degradation at 800 nM. When comparing both in vitro and in vivo therapeutic outcomes, D-PROTAC proved more effective than Defactinib in inhibiting tumor growth. Specifically, D-PROTAC at 800 nM reduced cell viability, migration, and invasion by approximately 80%. Additionally, in a subcutaneous A427 mouse model, D-PROTAC administered intratumorally at 10 mg/kg led to around 85% suppression of tumor growth. These findings represent the first demonstration that PROTACs could offer a promising therapeutic strategy for treating KRAS-mutant NSCLC, a particularly challenging form of cancer.