Mutations in RAS genes, which cause tumor growth in about a quarter of all cancer patients, are among the most infamous cancer drivers. Scientists have solved the molecular structure of SHOC2, a RAS-pathway protein, and two other proteins (that it binds to). The SHOC2-MRAS-PP1C (“SMP”) complex, a three-protein assembly, regulates the RAS signaling pathway and aids cancer cells with RAS mutations in survival.
The high-resolution structure of this complex, revealed by X-ray crystallography and cryogenic electron microscopy, suggests potential drug binding sites for inhibiting the RAS pathway and inhibiting cancer growth. The study reveals a potential therapeutic strategy for a signaling pathway that has previously been difficult to target with drugs.
The scientists learned a lot about how SHOC2 operates in the circuit by solving the structure, which points out potential therapeutic interventions.
The researchers also used deep mutational scanning to examine the effect of mutations in each amino acid of SHOC2 on the protein’s function. They could use the information to discover new links between SHOC2 mutations and other diseases.
The study will clarify the clinical significance of SHOC2 mutations and assist drug developers in developing compounds that bind to the SMP complex to inhibit SHOC2. It opens up promising avenues to create much-needed new therapies for RAS-mutant cancers.