Abstract 1753: SHOC2 is a genetic dependency in NRAS-mutant melanoma

Abstract

Abstract Melanoma is the most lethal form of skin cancer, with over 300,000 new cases worldwide every year. Specifically, melanoma with NRAS mutations are of particular clinical concern due to their association with a poor prognosis and lack of specific treatment options. Therefore, there is a pressing need for novel approaches to address the treatment of NRAS-mutant melanoma. A current approach to identify novel drug targets is based on the genetic concept of induced essentiality, where functional interactions that occur in response to oncogene addiction create a dependency on another gene. To identify genetic dependencies in NRAS-mutant melanoma, whole-genome CRISPR-Cas9 knockout screens were conducted in 6 NRAS-mutant and 7 NRAS-wild-type (wt) early-passage New Zealand melanoma (NZM) cell lines that were established and maintained at 5% oxygen to mimic physiological oxygen conditions. The NZM cell lines were stably transduced with the whole-genome Brunello lentiviral single guide (sg) RNA library and screened for up to 35 days. BAGEL (Bayesian Analysis of Gene Essentiality) analyses of the NZM whole-genome knockout screens, alongside CRISPR-Cas9 screening data using the Avana sgRNA library from an additional 28 melanoma cell lines, available on the Cancer Cell Line Encyclopaedia (CCLE) database, revealed prospective gene candidates that exhibit greater detrimental effects on the fitness of NRAS-mutant cell lines compared to the NRAS-wt lines. These genes are being further validated as essential genes for NRAS-mutant melanoma cells through custom sgRNA library knockout screens and in vitro individual gene knockout studies. In particular, we demonstrate that knockout of SHOC2, a gene that encodes a scaffold protein essential for activation of the MAPK signalling pathway, results in the prevention of ERK phosphorylation and a more substantial reduction in cell growth in NRAS-mutant NZM cell lines when compared to NRAS-wt lines. These results support previous studies that have identified SHOC2 as a potential therapeutic target for RAS-driven cancers and suggest that targeting of SHOC2 may have utility in NRAS-mutant melanoma, where greater treatment options are urgently needed. Citation Format: Andrea Y. Gu, Tet-Woo Lee, Aziza Khan, Francis W. Hunter, Dean C. Singleton, Stephen M. F. Jamieson. SHOC2 is a genetic dependency in NRAS-mutant melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1753.