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 2,3 . Nevertheless, KRAS G12C mutations account for only around 15% of KRAS -mutated cancers 4,5 , and there are no approved KRAS inhibitors for the majority of patients with tumours containing other common KRAS mutations. Here we describe RMC-7977, a reversible, tri-complex RAS inhibitor with broad-spectrum…

• UD
  U.S. Department of Defense

  Awards: P30 CA008748, W81XWH2110692
• UD
  U.S. Department of Health and Human Services

  Award: P30 CA008748
• PC
  Pew Charitable Trusts
• DR
  Damon Runyon Cancer Research Foundation

  Award: P30 CA008748
• PC
  Pancreatic Cancer Action Network

  Award: 22-WG-DERB
• BS
  Bristol-Myers Squibb
• EL
  Eli Lilly and Company
• GA
  Giovanni Armenise-Harvard Foundation
• MS
  Memorial Sloan-Kettering Cancer Center

  Award: CA008748
• PS
  Pershing Square Sohn Cancer Research Alliance

  Award: P30 CA008748
• DP
  Deciphera Pharmaceuticals
• MT
  Mirati Therapeutics
• RM
  Revolution Medicines
• ST
  Springworks Therapeutics
• EC
  European Commission

  Award: 101001288
• AI
  Associazione Italiana per la Ricerca sul Cancro

  Awards: IG 2021, 25737
• P
  Pharmaron
• NI
  National Institutes of Health

  Awards: 1R01CA23074501, P30 CA008748, R35CA232113, T32CA009156, 1R01CA23026701A1
• NC
  National Cancer Institute

  Awards: P50CA257911, CA008748, T32CA009156, P30 CA008748, R35CA232113