Abstract 3429: Synthetic lethal RNAi screens to nominate potential therapeutic combinations for uveal melanoma

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Uveal melanoma (UM) is the most common form of ocular cancer in adults and metastatic disease currently has no effective therapy. Over 80% of UM tumors harbor activating mutations in the heterotrimeric G protein α subunits GNAQ or GNA11. These mutations induce protein kinase C (PKC) and the MAP kinase pathway, which signals through RAF, MEK, and ERK. Clinical trials of MEK and PKC inhibitors are underway to treat UM, however, novel therapeutic strategies may be required for effective treatment. To identify rational combination therapies in the context of MEK or PKC inhibition, we performed a pooled, genome-wide synthetic lethal RNA interference screen. Candidate genes whose silencing sensitizes GNAQ/11-mutant UM cells to MEK or PKC inhibition were nominated and further validated across a panel of cell lines using a custom pool of shRNAs. Several genes scored well across all cell lines. The top MEK inhibitor sensitizer was BRAF, thereby highlighting the importance of MAPK signaling in UM. Several non-MAPK pathway genes were also nominated and may represent novel pathways for the development of combination therapies. Citation Format: Chelsea S. Place, Glenn S. Cowley, David E. Root, Levi A. Garraway. Synthetic lethal RNAi screens to nominate potential therapeutic combinations for uveal melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3429. doi:10.1158/1538-7445.AM2014-3429