Genome-wide CRISPR screen identifies a novel target in NRAS-driven melanoma microbiologystudy

Researchers at Novartis BioMedical Research in the US and Switzerland have identified a molecular target that may provide a new therapeutic pathway for cancers driven by NRAS mutations. Findings suggest that interfering with specific protein interactions could disrupt signaling pathways associated with uncontrolled cell proliferation in malignancies lacking targeted treatments.

KRAS and NRAS are members of the RAS family of genes, which encode proteins that regulate cell growth and division through signaling pathways. Mutations in these genes disrupt normal signaling, leading to oncogenesis. Codon 12 mutations in KRAS are common in solid tumors, while codon 61 mutations in NRAS are predominantly associated with melanoma.

Targeted therapies have been developed for KRAS(G12C) and KRAS(G12D) mutations, yet effective strategies for NRAS-mutant cancers remain elusive. NRAS mutations account for 20–30% of melanoma cases, representing a substantial therapeutic gap, particularly given the absence of approved targeted therapies for this subset.

With 50,000 new cases annually in the US and Europe, NRAS-mutant melanoma continues to present an unmet clinical need. Identifying specific molecular dependencies associated with these mutations could reveal new therapeutic targets and inform treatment strategies for NRAS-driven malignancies.

In the study, “Targeting the SHOC2–RAS interaction in RAS-mutant cancers,” published in Nature, researchers conducted a genome-wide CRISPR screen to identify genetic dependencies associated with NRAS(Q61*) mutations.

Ba/F3 cell lines engineered to express KRAS and NRAS mutations at codons 12 and 61 were used to model RAS/MAPK oncogenic addiction in the absence of other genetic alterations.

A genome-wide lentiviral sgRNA library assessed growth dependencies of KRAS and NRAS mutant lines under controlled conditions. Mutant- and isoform-selective dependencies were then confirmed using small-molecule inhibitors specific to KRAS(G12C) and KRAS(G12D). Subsequent analysis focused on identifying genetic vulnerabilities unique to NRAS(Q61*) mutants.

SHOC2 emerged as a significant dependency in NRAS(Q61*)-mutant models. In Ba/F3 cell lines, sgRNA-mediated SHOC2 knockout led to pronounced cell lethality, with NRAS(Q61*) mutants exhibiting heightened sensitivity compared to KRAS(G12*)-mutant lines.

In melanoma xenograft models, SHOC2 depletion resulted in tumor growth inhibition comparable to that observed following NRAS knockdown, suggesting that targeting SHOC2 could disrupt MAPK signaling in NRAS-driven malignancies.

Analysis of melanoma xenograft models further demonstrated that SHOC2 depletion substantially reduced tumor growth in NRAS(Q61*)-mutant settings. Reduced cell proliferation and decreased MAPK signaling were observed in vitro following SHOC2 knockdown, aligning with the in vivo findings.

Mechanistic studies confirmed that SHOC2 forms a direct interaction with both NRAS(Q61R) and KRAS(Q61R), with similar binding affinities. Structural optimization efforts led to the identification of small-molecule compounds capable of binding SHOC2 and disrupting the SHOC2–RAS interaction, with one compound demonstrating a dose-dependent inhibition of RAS/MAPK signaling in NRAS(Q61*)-mutant melanoma cells.

Targeting SHOC2 in NRAS(Q61)-mutant cancer presents a therapeutic strategy distinct from direct RAS targeting, potentially impeding cancer cell signaling through SHOC2–RAS interaction disruption.

Identifying small-molecule binders to SHOC2 illustrates its druggable potential in NRAS-driven melanoma, with broader implications for other RAS-mutant cancers where SHOC2 regulates MAPK signaling.

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