Resistance to certain KRAS G12C inhibitors can result from the buildup of active, GTP-bound RAS, which can increase tumor growth in cancer patients. Therefore, effectively blocking active RAS becomes crucial. In a recent study, researchers led by Ferdinandos Skoulidis, M.D., Ph.D., and Haniel Araujo, M.D., evaluated the antitumor effects of a new class of inhibitors that target the active form of RAS proteins: RMC-7977, a pan-RAS inhibitor of KRAS/HRAS/NRAS, and RMC-4998, a RAS G12C-selective inhibitor.
Active RAS inhibition resulted in robust and sustained tumor shrinkage across multiple difficult-to-treat, treatment-resistant lung cancer models. Combining the two inhibitors induced cures in some models. In addition, the study revealed a mucinous program in tumor cells that supports RAS inhibitor tolerance and may predict poor response to FDA-approved KRAS G12C inhibitors sotorasib or adagrasib in patients with advanced KRAS G12C-mutant non-small cell lung cancer. These findings may aid in developing personalized strategies and improving RAS inhibitor treatments for patients with lung cancer.