Genetic disruption of oncogenic Kras sensitizes lung cancer cells to Fas receptor-mediated apoptosis

Significance Oncogenic KRAS underlies 30–90% of lung, colon, and pancreatic cancers, but despite more than 30 y of research, clinical inhibitors of KRAS—and potential resistance mechanisms—remain elusive. Using CRISPR-mediated genome editing of oncogenic Kras , we show that some lung cancer cells can survive Kras knockout, indicating the existence of mechanisms that allow tumors to escape Kras oncogene addiction. We identify genes highly expressed in Kras knockout cells, including the Fas receptor gene. Antibodies that activate Fas receptor selectively induced apoptosis in Kras-independent lung cancer cells, suggesting a potential strategy for combinatorial therapies against Kras-driven tumors. These findings have direct translational implications for the treatment of lung cancer and other KRAS mutant cancer types.