1214 Targeting SHOC2 disrupts MEK/ERK signaling and inhibits viability of NRAS-mutant human melanoma cells

Invasive melanoma is projected to become the second-most common cancer in US and most men by 2030. NRAS-mutant melanomas are subtype lacking effective molecularly targeted therapies. Multiple synthetic lethal screens have identified SHOC2 as an essential cooperator with oncogenic RAS. Previous data from our group shown that RAS activates MAPK signaling forming a trimeric complex PP1C, crystal structure of which was recently high resolution using cryo-electron microscopy x-ray crystallography others. In present study, we investigate functional effect targeting expression human cells. Small interfering RNA (siRNA) directed against used determine knockdown on cell viability SK-MEL-30 SK-MEL-2 lines. NRAS wild-type A375 MeWo lines were controls. Immunoblot analysis Ras effector phosphoproteins performed verify downstream effects. The allosteric MEK1/2 inhibitor trametinib pharmacologic MEK inhibition combination knockdown. We found inhibited MEK, ERK, AKT activity, well contrast, BRAF V600E-mutant cells resistant inhibition. Furthermore, resulted maximal MEK/ERK growth inhibition, induction apoptosis These results indicate feasible therapeutic target melanoma. Further preclinical clinical studies utilizing warranted