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Ref Type Journal Article
PMID (38236605)
Authors Rubinson DA, Tanaka N, Fece de la Cruz F, Kapner KS, Rosenthal MH, Norden BL, Barnes H, Ehnstrom S, Morales-Giron AA, Brais LK, Lemke CT, Aguirre AJ, Corcoran RB
Title Sotorasib is a pan-RASG12C inhibitor capable of driving clinical response in NRASG12C cancers.
Journal Vol Issue Date Pages Journal Short Title
Cancer discovery 2024 Jan 18 Cancer Discov
URL
Abstract Text 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.

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