HRAS promotes mutant NRAS-driven transformation with codon and allele specificity.

Authors

Hyun Lee, Jacob M Hughes, Joseph P LaMorte, Bridget A Finniff, Picabo Binette, Sarasi K Gunasekara, Ariana Covas, Vanessa E Wall, Dominic Esposito, Matthew D Wilkerson, Marielle E Yohe, Robert L Kortum

Published in

Science signaling. Volume 19. Issue 954. Pages eaej6209. Sep 08, 2026. Epub Sep 08, 2026.

Abstract

Wild-type RAS family members determine the signaling and therapeutic response in cancers driven by mutant HRAS and KRAS because they activate alternate RAS effector pathways. Here, we found that the requirement for wild-type RAS to support mutant NRAS-driven transformation correlated with codon-specific differences in GTP hydrolysis. NRAS with mutations at either Gly¹² (G12X) or Gly¹³ (G13X), which retained the GDP-GTP cycling function, had modest autonomous transforming potential. In contrast, NRAS with GTP-locking mutations at Gln⁶¹ (Q61X mutants) was uncoupled from receptor tyrosine kinase (RTK) input, rendering wild-type RAS an obligate partner for RTK-stimulated signaling and oncogenesis. In RASless cells expressing mutant NRAS, reintroduction of wild-type HRAS was sufficient to restore signaling and transformation. Global dependency mapping in human cancer cells revealed functional partitioning, wherein mutant NRAS promoted MAPK signaling and wild-type HRAS promoted PI3K-AKT survival signaling. Consequently, allele-specific or pan-RAS(ON) inhibitors synergized with inhibitors of proximal RTK signaling or of wild-type HRAS or KRAS to overcome this signaling plasticity. Pan-RAS(ON) and HRAS inhibition was synergistic for all NRAS mutants tested, with Q61X mutants showing greater sensitivity. These findings define the signaling partnership between mutant NRAS and wild-type HRAS as a targetable vulnerability and provide a biochemical blueprint for dual RAS inhibition in NRAS-mutated malignancies.

PMID:
42709866
Bibliographic data and abstract were imported from PubMed on 09 Sep 2026.

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