Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy

Abstract RAS oncogenes (collectively NRAS , HRAS , and especially KRAS ) are among the most frequently mutated genes in cancer, with common driver mutations occurring at codons 12, 13 and 61 1 . Small molecule inhibitors of the KRAS G12C oncoprotein have demonstrated clinical efficacy in patients with multiple cancer types and have led to regulatory approvals for the treatment of non-small-cell lung cancer (NSCLC) 2,3 . Nevertheless, KRAS G12C mutations account for only ~14% of KRAS mutated cancers 4 and there are no approved KRAS inhibitors for the majority of patients with tumors harboring other common RAS mutations. Here, we describe RMC-7977, a reversible, tri-complex RAS inhibitor with broad spectrum activity for both mutant and wild-type (WT) KRAS, NRAS, and HRAS variants (a RAS MULTI (ON) inhibitor). Preclinically, RMC-7977 demonstrated potent activity against RAS-addicted tumors carrying various RAS genotypes, particularly cancer models with KRAS codon 12 mutations ( KRAS G12X ). RMC-7977 led to tumor regressions and was well tolerated in diverse RAS-addicted preclinical cancer models. Additionally, RMC-7977 inhibited the growth of KRAS G12C cancer models that are resistant to KRAS G12C inhibitors due to restoration of RAS pathway signaling. Thus, RAS MULTI (ON) inhibitors can target multiple oncogenic and WT RAS isoforms and hold the potential to treat a wide range of RAS-addicted cancers with high unmet clinical need. A related RAS MULTI (ON) inhibitor, RMC-6236, is currently under clinical evaluation in patients with KRAS G12X mutant solid tumors (NCT05379985).