1. Academic Validation
  2. Sotorasib is a pan-RASG12C inhibitor capable of driving clinical response in NRASG12C cancers

Sotorasib is a pan-RASG12C inhibitor capable of driving clinical response in NRASG12C cancers

  • Cancer Discov. 2024 Jan 18. doi: 10.1158/2159-8290.CD-23-1138.
Douglas A Rubinson 1 Noritaka Tanaka 2 Ferran Fece de la Cruz 3 Kevin S Kapner 4 Michael H Rosenthal 5 Bryanna L Norden 6 Haley Barnes 7 Sara Ehnstrom 2 Alvin A Morales-Giron 7 Lauren K Brais 1 Christopher T Lemke 8 Andrew J Aguirre 1 Ryan B Corcoran 2


  • 1 Dana-Farber Cancer Institute, Boston, MA, United States.
  • 2 Massachusetts General Hospital, Boston, MA, United States.
  • 3 Massachusetts General Hospital Cancer Center, Boston, MA, United States.
  • 4 Dana-Farber/Harvard Cancer Center, Boston, United States.
  • 5 Dana-Farber/Harvard Cancer Center, Boston, MA, United States.
  • 6 Massachusetts General Hospital, Charleston, MA, United States.
  • 7 Massachusetts General Hospital, Boston, Massachusetts, United States.
  • 8 Broad Institute, United States.

KRASG12C inhibitors, like sotorasib and adagrasib, potently and selectively inhibit KRASG12C through a covalent interaction with the mutant cysteine, driving clinical efficacy in KRASG12C tumors. Since amino acid sequences of the three main Ras isoforms-KRAS, NRAS and HRAS-are highly similar, we hypothesized that some KRASG12C inhibitors might also target NRASG12C and/or HRASG12C, which are less common but critical oncogenic driver mutations in some tumors. While some inhibitors, like adagrasib, were highly selective for KRASG12C, Others also potently inhibited NRASG12C and/or HRASG12C. Notably, sotorasib was 5-fold more potent against NRASG12C compared to KRASG12C or HRASG12C. Structural and reciprocal mutagenesis studies suggested that differences in isoform-specific binding are mediated by a single amino acid: Histidine-95 in KRAS (Leucine-95 in NRAS). A patient with NRASG12C colorectal Cancer treated with sotorasib and the anti-EGFR antibody panitumumab achieved a marked tumor response, demonstrating that sotorasib can be clinically effective in NRASG12C-mutated tumors.