USP7 deubiquitinates KRAS and promotes non-small cell lung cancer.

RAS oncogenic mutations are pivotal drivers of tumorigenesis. Ubiquitination modulates RAS functions, including activation, stability, and localization. While several E3 ligases regulate RAS ubiquitination, RAS deubiquitination remains less understood. Our study reveals that ubiquitin-specific protease 7 (USP7) directly deubiquitinates KRAS, stabilizing it and promoting the proliferation of non-small cell lung cancer (NSCLC) cells. Mechanistically, USP7 binds KRAS via its TRAF domain and removes the K48-linked polyubiquitin chains from residue K147. In addition, USP7 also stabilizes oncogenic KRAS mutants through deubiquitination. In lung cancer tissues, high USP7 expression is positively correlated with KRAS and is associated with lower patient survival rates. Moreover, USP7 inhibitors suppress NSCLC cell proliferation, particularly in cells resistant to the KRAS-G12C inhibitor AMG510. In conclusion, our findings identify USP7 as a key deubiquitinase regulating RAS stability, and targeting USP7 is a promising strategy to counteract KRAS inhibitor resistance in NSCLC.