Novel Target Identified for NRAS-Driven Melanoma via Genome-Wide CRISPR Screen

Researchers from Novartis BioMedical Research in the United States and Switzerland have uncovered a promising new therapeutic target for melanomas driven by NRAS mutations. Using a comprehensive genome-wide CRISPR screening approach, the scientists identified the protein SHOC2 as a critical dependency in NRAS-mutant melanoma models. Disruption of SHOC2 through genetic knockout significantly impaired tumor growth by inhibiting the MAPK signaling pathway, which is often hyperactive in these cancers.

NRAS, part of the RAS gene family, encodes proteins that regulate vital cell growth and division processes. Mutations in NRAS, particularly at codon 61, are common in melanoma, representing approximately 20-30% of cases. Unlike KRAS mutations, which have targeted therapies available, effective treatments for NRAS-mutant cancers have been limited, creating an urgent need for new strategies.

The study utilized Ba/F3 cell lines engineered to express mutant forms of KRAS and NRAS to simulate RAS/MAPK dependency. A library of sgRNAs was employed to evaluate which genes are essential for the proliferation of these mutant cells. SHOC2 emerged as a prominent vulnerability; its knockout caused pronounced cell death in NRAS(Q61*) models, with lesser effects on KRAS mutants.

Further validation in melanoma xenograft models revealed that reducing SHOC2 levels markedly suppressed tumor growth, matching the effects seen with direct NRAS suppression. In vitro analyses demonstrated that SHOC2 physically interacts with mutant NRAS and KRAS proteins, forming complexes that facilitate MAPK pathway activation. Small-molecule compounds designed to disrupt this interaction successfully inhibited RAS signaling, indicating druggability of this pathway.

This approach offers an innovative therapeutic avenue distinct from direct RAS targeting, which has historically posed challenges. Targeting SHOC2 could effectively hinder tumor progression in NRAS-driven melanoma and potentially other RAS-mutant cancers. The development of molecules capable of interfering with SHOC2-RAS interactions marks a promising step toward precision therapies for these aggressive malignancies.

These findings, published in Nature, highlight the therapeutic potential of disrupting specific protein interactions involved in oncogenic signaling pathways. With further research and drug development, SHOC2 inhibitors might become an effective treatment modality for patients with NRAS-mutant melanoma, filling a significant gap in current cancer therapy options.

Source: https://medicalxpress.com/news/2025-05-genome-wide-crispr-screen-nras.html