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<p>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 (&lt; 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.</p>

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RAS inhibition limits oncogenic signaling and tumorigenesis in neuroblastoma regardless of RAS mutational status

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月31日

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  • Mubashir Mintoo,
  • Vinodh Rajagopalan,
  • Rachel Greathouse,
  • Cecile Nasarre,
  • Tarah Trebino,
  • Dianicha Santana,
  • Kevin O. Flores-Galvez,
  • Gayatri Ketavarapu,
  • Akiko Koide,
  • Fiona E. Hood,
  • Ian A. Prior,
  • Mark R. Philips,
  • Shohei Koide,
  • Bill Chiu,
  • John P. O’Bryan

摘要

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.