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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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NRAS G12C Advanced Solid Tumor sensitive Sotorasib Preclinical - Cell culture Actionable In a preclinical study, Lumakras (sotorasib) inhibited viability of cultured cells expressing NRAS G12C (PMID: 38236605). 38236605
NRAS G12C colorectal cancer predicted - sensitive Panitumumab + Sotorasib Case Reports/Case Series Actionable In clinical case study, treatment with the combination of Lumakras (sotorasib) and Vectibix (panitumumab) resulted in a decrease in the size of liver metastases and improved serum markers after 2 months of treatment in a patient with colorectal cancer harboring NRAS G12C (PMID: 38236605). 38236605
HRAS G12C Advanced Solid Tumor sensitive JDQ443 Preclinical - Cell culture Actionable In a preclinical study, JDQ443 inhibited viability of cultured cells expressing HRAS G12C (PMID: 38236605). 38236605
HRAS G12C Advanced Solid Tumor sensitive Sotorasib Preclinical - Cell culture Actionable In a preclinical study, Lumakras (sotorasib) inhibited viability of cultured cells expressing HRAS G12C (PMID: 38236605). 38236605
NRAS G12C Advanced Solid Tumor sensitive RM-018 Preclinical - Cell culture Actionable In a preclinical study, RM-018 inhibited viability of cultured cells expressing NRAS G12C (PMID: 38236605). 38236605
NRAS G12C Advanced Solid Tumor sensitive JDQ443 Preclinical - Cell culture Actionable In a preclinical study, JDQ443 inhibited viability of cultured cells expressing NRAS G12C (PMID: 38236605). 38236605
NRAS G12C leukemia predicted - sensitive Sotorasib Preclinical - Biochemical Actionable In a preclinical study, Lumakras (sotorasib) inhibited downstream signaling in leukemia cells harboring NRAS G12C in culture (PMID: 38236605). 38236605
HRAS G12C Advanced Solid Tumor sensitive RM-018 Preclinical - Cell culture Actionable In a preclinical study, RM-018 inhibited viability of cultured cells expressing HRAS G12C (PMID: 38236605). 38236605