2. Academic Validation
  3. 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
Affiliations

Affiliations

  • 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.
PMID: 38236605 DOI: 10.1158/2159-8290.CD-23-1138
Abstract

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.

Figures
Products