Targeting the SHOC2–RAS interaction in RAS-mutant cancers

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 a direct interaction with SHOC2, evidenced by X-ray co-crystal structure. In vitro high-throughput screening enabled the discovery of small molecules that bind to SHOC2 and disrupt the interaction with NRAS(Q61*). Structure-based optimization led to a cellularly active tool compound that shows inhibition of mitogen-activated protein kinase (MAPK) signalling and proliferation in RAS-mutant cancer models, most notably in NRAS(Q61*) settings. These findings provide evidence for a neomorph SHOC2–(canonical)RAS protein interaction that is pharmacologically actionable and relevant to cancer sustenance. Overall, this work provides the concept validation and foundation for developing new therapies at the core of the RAS signalling pathway.