Activity of Direct KRAS(G12C) Inhibitors in Preclinical Models of Pediatric Cancer

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 K-, H-, 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 H- and NRAS(G12C) has not been completely characterized. Here, 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 H- and NRAS(G12C). Sotorasib and RMC-6291 decreased ERK phosphorylation in cells expressing H-, K-, 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 H- or NRAS(G12C)-altered malignancies in addition to those with KRAS(G12C)-altered malignancies.

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Publication Details

Journal
Molecular Cancer Therapeutics
Published
2025-12-04
DOI
https://doi.org/10.1158/1535-7163.mct-25-0022
Citations
1
Primary Topic
Protein Kinase Regulation and GTPase Signaling
Type
article
Field-Weighted Citation Impact
0.81
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article

Activity of Direct KRAS(G12C) Inhibitors in Preclinical Models of Pediatric Cancer

Jack F. Shern, Patience Odeniyide, Lisa M. Miller Jenkins, Marielle E. Yohe et al.
1 citations
Molecular Cancer Therapeutics
Protein Kinase Regulation and GTPase Signaling
0.81
article

Activity of Direct KRAS(G12C) Inhibitors in Preclinical Models of Pediatric Cancer

Jack F. Shern, Patience Odeniyide, Lisa M. Miller Jenkins, Marielle E. Yohe, Stacey Stauffer, Kristine A. Isanogle, Andrew Baker, Edjay R. Hernandez, Robert L. Kortum, Andrew J. Perciaccante, Hannah Price, Elijah F. Edmondson, Simone Difilippantonio, William Burgan, Christine A. Pratilas, Kent L. Rossman, Connor P. Jewell, Ashwaq K. Aljabri, Hyun Jung Lee, Ying Wu, Lucas Stauffer, Katie Powell
article en
1 citations

Abstract

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 K-, H-, 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 H- and NRAS(G12C) has not been completely characterized. Here, 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 H- and NRAS(G12C). Sotorasib and RMC-6291 decreased ERK phosphorylation in cells expressing H-, K-, 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 H- or NRAS(G12C)-altered malignancies in addition to those with KRAS(G12C)-altered malignancies.

Molecular Cancer Therapeutics
University of North Carolina at Chapel Hill (US), Leidos (United States) (US), Johns Hopkins University (US), Uniformed Services University of the Health Sciences (US), Johns Hopkins Medicine (US), Frederick National Laboratory for Cancer Research (US), National Cancer Institute (US), Center for Cancer Research (US), Sidney Kimmel Comprehensive Cancer Center (US), Leidos Biomedical Research Inc. (United States)
Openalex Percentile: Top 21%
Protein Kinase Regulation and GTPase Signaling
0.81
DOIOpen Access PDFOpenAlex
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