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Ref Type Journal Article
PMID (41340466)
Authors Price HE, Stauffer S, Lee H, Isanogle KA, Wu Y, Powell K, Baker A, Stauffer L, Perciaccante AJ, Jewell CP, Hernandez ER, Aljabri AK, Odeniyide P, Pratilas CA, Burgan W, Edmondson EF, Difilippantonio S, Kortum RL, Shern JF, Jenkins LM, Rossman KL, Yohe ME
Title Activity of Direct KRAS(G12C) Inhibitors in Preclinical Models of Pediatric Cancer.
Journal Vol Issue Date Pages Journal Short Title
Molecular cancer therapeutics 25 5 2026 May 04 727-744 Mol Cancer Ther
URL
Abstract Text Directly targeting RAS is a promising approach for the treatment of RAS-altered malignancies. Recently, several groups have developed mutation-specific agents such as sotorasib and adagrasib, which directly target KRAS by covalently modifying KRAS(G12C). KRAS is commonly altered in adult malignancies, such as lung, pancreatic, and colorectal adenocarcinomas, but is less commonly altered in pediatric cancers. However, rare pediatric solid tumors harboring KRAS(G12C), HRAS(G12C), or NRAS(G12C) have been observed, including rhabdomyosarcoma and neuroblastoma tumors, as well as leukemias. The efficacy of KRAS(G12C) inhibitors in pediatric malignancies is currently unknown, and the ability of these drugs to modify HRAS(G12C) and NRAS(G12C) has not been completely characterized. In this study, we show that sotorasib, adagrasib, and the RAS-ON inhibitor RMC-6291 are effective in a neuroblastoma cell line altered by KRAS(G12C). We further demonstrated that sotorasib and adagrasib inhibited SOS-mediated guanine nucleotide exchange on HRAS(G12C) and NRAS(G12C). Sotorasib and RMC-6291 decreased ERK phosphorylation in cells expressing HRAS(G12C), KRAS(G12C), or NRAS(G12C). Importantly, sotorasib also decreased ERK phosphorylation in a NRAS(G12C)-altered cell line xenograft model; however, this treatment did not prolong survival as a single agent. These results suggest that combinations of targeted agents that include sotorasib may be required for clinical benefit in pediatric patients with HRAS(G12C)- or NRAS(G12C)-altered malignancies, in addition to those with KRAS(G12C)-altered malignancies.

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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
MAP2K1 D67N NRAS G12C PTEN del T-cell acute lymphoblastic leukemia no benefit Sotorasib Preclinical - Cell line xenograft Actionable In a preclinical study, Lumakras (sotorasib) treatment resulted in decreased Erk1/2 phosphorylation, but demonstrated only a modest effect on viability in a T-cell acute lymphoblastic leukemia cell line harboring NRAS G12C, MAP2K1 D67N, and PTEN deletion in culture, and inhibited Erk1/2 phosphorylation levels in liver-infiltrating cancer cells but did not prolong survival in a cell line xenograft model (PMID: 41340466). 41340466
NRAS G12C acute myeloid leukemia sensitive Sotorasib Preclinical - Cell culture Actionable In a preclinical study, Lumakras (sotorasib) treatment resulted in decreased Erk1/2 phosphorylation, cell cycle arrest, and decreased viability in an acute myeloid leukemia cell line harboring NRAS G12C in culture (PMID: 41340466). 41340466
HRAS G12C head and neck carcinoma no benefit Sotorasib Preclinical - Cell culture Actionable In a preclinical study, Lumakras (sotorasib) treatment resulted in decreased Erk1/2 phosphorylation at high concentrations, but did not inhibit proliferation in a head and neck carcinoma cell line harboring HRAS G12C in culture (PMID: 41340466). 41340466
HRAS G12C Advanced Solid Tumor sensitive Sotorasib Preclinical - Cell culture Actionable In a preclinical study, Lumakras (sotorasib) inhibited Erk1/2 phosphorylation and viability in cells expressing HRAS G12C in culture (PMID: 41340466). 41340466
HRAS G12C HRAS T58I rhabdomyosarcoma resistant Sotorasib Preclinical - Cell culture Actionable In a preclinical study, a rhabdomyosarcoma cell line harboring HRAS G12C and HRAS T58I was resistant to Lumakras (sotorasib) in culture (PMID: 41340466). 41340466
HRAS G12C HRAS T58I rhabdomyosarcoma resistant RMC-6291 Preclinical - Cell culture Actionable In a preclinical study, a rhabdomyosarcoma cell line harboring HRAS G12C and HRAS T58I was resistant to RMC-6291 treatment in culture (PMID: 41340466). 41340466
HRAS G12C head and neck carcinoma sensitive RMC-6291 Preclinical - Cell culture Actionable In a preclinical study, treatment with RMC-6291 inhibited Erk1/2 phosphorylation and viability in a head and neck carcinoma cell line harboring HRAS G12C in culture (PMID: 41340466). 41340466
MAP2K1 D67N NRAS G12C PTEN del T-cell acute lymphoblastic leukemia sensitive Copanlisib + Sotorasib Preclinical - Cell culture Actionable In a preclinical study, Lumakras (sotorasib) and Aliqopa (copanlisib) synergistically inhibited viability in a T-cell acute lymphoblastic leukemia cell line harboring NRAS G12C, MAP2K1 D67N, and PTEN deletion in culture (PMID: 41340466). 41340466
NRAS G12C acute myeloid leukemia sensitive RMC-6291 Preclinical - Cell culture Actionable In a preclinical study, treatment with RMC-6291 inhibited Erk1/2 phosphorylation and viability in an acute myeloid leukemia cell line harboring NRAS G12C in culture (PMID: 41340466). 41340466
NRAS G12C Advanced Solid Tumor sensitive Sotorasib Preclinical - Cell culture Actionable In a preclinical study, Lumakras (sotorasib) inhibited Erk1/2 phosphorylation and viability in cells expressing NRAS G12C in culture (PMID: 41340466). 41340466