Abstract P180: Genetic screen identifies PDPK1 as a synergistic target to enhancing the efficacy of MEK1/2 inhibitors in NRAS mutant melanoma

Abstract

Abstract Melanomas frequently harbor activating NRAS mutations; however, there has been little advance in targeted therapy options for NRAS mutant melanoma patients. MEK inhibitors (MEKi) showed modest efficacy in clinic, which is insufficient to be approved by FDA. In this study, we performed a genome-wide CRISPR/Cas9-based screening, identified PDPK1 (Phosphoinositide-dependent kinase-1) as a therapeutic target to enhancing the efficacy of MEKi, and validated it in various NRAS mutant melanoma cell lines via pharmacological and genetic approaches. Combined inhibition of PDPK1 and MEK (PDPK1i+MEKi) profoundly inhibited NRAS mutant tumor growth in a xenograft model. Notably, the combinatorial treatment induced pyroptosis, and increased ratio of intratumoral CD8+ T cells, delayed tumor growth and prolonged survival in an immune competent allograft model whereas it showed a significantly weaker potency in an isogenic immune deficient model. These data suggest PDPK1i + MEKi is an efficient strategy against NRAS mutant melanoma in an immune-response-dependent manner. Significance: NRAS is still an 'undruggable' target in melanoma. Our discovery rationalizes the clinical development of PDPK1i plus MEKi in NRAS mutant melanoma patients and suggests further synergy of targeted therapy and immunotherapy. Citation Format: Weijia Cai, Mai Nguyen, nicole wilski, timothy purwin, Manoela TiagodosSantos, Andrew Aplin. Genetic screen identifies PDPK1 as a synergistic target to enhancing the efficacy of MEK1/2 inhibitors in NRAS mutant melanoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P180.