Targeting the SHOC2-RAS interaction in RAS-mutant cancers.

ABSTRACT: Activating mutations in the rat sarcoma (RAS) genes HRAS, NRAS and KRAS collectively represent the most frequent oncogenic driver in human cancer¹. They have previously been considered undruggable, but advances in the past few years have led to the clinical development of agents that target KRAS(G12C) and KRAS(G12D) mutants, yielding promises of therapeutic responses at tolerated doses². However, clinical agents that selectively target NRAS(Q61*) mutants (* represents 'any'), the second-most-frequent oncogenic driver in melanoma, are still lacking. Here we identify SHOC2, a component of the SHOC2-MRAS-PP1C complex, as a dependency of RAS(Q61*) tumours in a nucleotide-state-dependent and isoform-agnostic manner. Mechanistically, we found that oncogenic NRAS(Q61R) forms

SUBMITTER: Hauseman ZJ 

PROVIDER: S-EPMC12137120 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature