Reference Detail

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	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	Sotorasib	Preclinical - Cell culture	Actionable	In a preclinical study, Lumakras (sotorasib) inhibited viability of cultured cells expressing NRAS G12C (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
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
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
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	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	Sotorasib	Preclinical - Cell culture	Actionable	In a preclinical study, Lumakras (sotorasib) inhibited viability of cultured cells expressing HRAS G12C (PMID: 38236605).	38236605