RAS inhibition limits oncogenic signaling and tumorigenesis in neuroblastoma regardless of RAS mutational status
9 affiliations
- 1Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas St. MSC 955, Rm HO712E, Charleston, SC 29425 USA
- 2Ralph H. Johnson VA Medical Center, Charleston, SC 29401 USA
- 3Department of Surgery, Division of Pediatric Surgery, Stanford University, Stanford, CA 94305 USA
- 4Department of Pharmacology, University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL 60612 USA
- 5Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016 USA
- 6Department of Medicine, New York University School of Medicine, New York, NY 10016 USA
- 7Cellular and Molecular Physiology, Institute of Systems Molecular and Integrative Biology, University of Liverpool, Crown St, Liverpool, L69 3BX UK
- 8Molecular and Clinical Cancer Medicine, Institute of Systems Molecular and Integrative Biology, University of Liverpool, Crown St, Liverpool, L69 3BX UK
- 9Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016 USA
Abstract
Neuroblastoma (NBL) is a rare and aggressive pediatric malignancy with a 5-year survival rate of 40–50% for patients diagnosed with high-risk disease. NBLs arise in the sympathetic nervous system and causes 11% of all pediatric cancer deaths. MYCN amplification or overexpression drives 22% of NBL cases while deregulation of genes including c-MYC, ALK, PHOX2B, and LIN28B also plays a critical role in NBL initiation and progression. Although RAS proto-oncogenes are rarely mutated in primary NBL (< 2%), studies suggest that elevated RAS activity may contribute to NBL tumorigenesis and progression. Here, we explore targeted RAS inhibition as a potential therapeutic strategy for NBL. Using mutation-specific inhibitors of KRAS, we demonstrate the importance of mutant KRAS in NBL. Furthermore, using anti-RAS biologics and a pan RAS inhibitor, we also demonstrate the importance of wild type (WT) RAS activity in non-RAS mutant NBLs. Direct RAS inhibition decreases NBL cell proliferation, colony formation, and migration in vitro in NBL lines differing in MYCN and RAS mutation status. Furthermore, inhibition of WT RAS suppresses the growth of specific NBL lines in vivo. Our findings suggest that targeted RAS inhibition, even in the absence of RAS mutation, may represent a promising therapeutic approach for NBL patients.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1038/s41598-026-63488-x.
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BibTeX
@article{mintoo2026inhibition,
title = {{RAS inhibition limits oncogenic signaling and tumorigenesis in neuroblastoma regardless of RAS mutational status}},
author = {Mubashir Mintoo and Vinodh Rajagopalan and Rachel Greathouse and Cecile Nasarre and Tarah Trebino and Dianicha Santana and Kevin O. Flores-Galvez and Gayatri Ketavarapu and Akiko Koide and Fiona E. Hood and Ian A. Prior and Mark R. Philips and Shohei Koide and Bill Chiu and John P. O’Bryan},
journal = {Scientific Reports},
year = {2026},
month = jul,
doi = {10.1038/s41598-026-63488-x},
url = {https://doi.org/10.1038/s41598-026-63488-x},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - RAS inhibition limits oncogenic signaling and tumorigenesis in neuroblastoma regardless of RAS mutational status
AU - Mubashir Mintoo
AU - Vinodh Rajagopalan
AU - Rachel Greathouse
AU - Cecile Nasarre
AU - Tarah Trebino
AU - Dianicha Santana
AU - Kevin O. Flores-Galvez
AU - Gayatri Ketavarapu
AU - Akiko Koide
AU - Fiona E. Hood
AU - Ian A. Prior
AU - Mark R. Philips
AU - Shohei Koide
AU - Bill Chiu
AU - John P. O’Bryan
PY - 2026
DA - 2026/07/31
JO - Scientific Reports
DO - 10.1038/s41598-026-63488-x
UR - https://doi.org/10.1038/s41598-026-63488-x
AB - Neuroblastoma (NBL) is a rare and aggressive pediatric malignancy with a 5-year survival rate of 40–50% for patients diagnosed with high-risk disease. NBLs arise in the sympathetic nervous system and causes 11% of all pediatric cancer deaths. MYCN amplification or overexpression drives 22% of NBL cases while deregulation of genes including c-MYC, ALK, PHOX2B, and LIN28B also plays a critical role in NBL initiation and progression. Although RAS proto-oncogenes are rarely mutated in primary NBL (< 2%), studies suggest that elevated RAS activity may contribute to NBL tumorigenesis and progression. Here, we explore targeted RAS inhibition as a potential therapeutic strategy for NBL. Using mutation-specific inhibitors of KRAS, we demonstrate the importance of mutant KRAS in NBL. Furthermore, using anti-RAS biologics and a pan RAS inhibitor, we also demonstrate the importance of wild type (WT) RAS activity in non-RAS mutant NBLs. Direct RAS inhibition decreases NBL cell proliferation, colony formation, and migration in vitro in NBL lines differing in MYCN and RAS mutation status. Furthermore, inhibition of WT RAS suppresses the growth of specific NBL lines in vivo. Our findings suggest that targeted RAS inhibition, even in the absence of RAS mutation, may represent a promising therapeutic approach for NBL patients. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1038/s41598-026-63488-x.
SN - 2045-2322
ER -