Abstract LB-113: MAPK pathway suppression unmasks latent DNA repair defects and confers a chemical synthetic vulnerability inBRAF,NRASandNF1-mutant melanomas

Abstract

Abstract While the majority of BRAF-mutant melanomas respond to BRAF/MEK inhibitors, these agents are not typically curative. Moreover, they are largely ineffective in NRAS and NF1-mutant tumors. Here we report that genetic and chemical suppression of HDAC3 potently cooperates with MAPK pathway inhibitors in all three Ras pathway-driven tumors. Specifically, we show that entinostat dramatically enhances tumor regression when combined with BRAF/MEK inhibitors, both in models that are sensitive or relatively resistant to these agents. Interestingly, MGMT expression predicts responsiveness and marks tumors with latent defects in DNA repair. BRAF/MEK inhibitors enhance these defects by suppressing homologous recombination genes, inducing a BRCA-like state; however, entinostat addition triggers the concomitant suppression of NHEJ genes, resulting in a chemical synthetic lethality caused by excessive DNA damage. Together these studies identify melanomas with latent DNA repair defects, describe a promising drug combination that capitalizes on these defects, and reveal a tractable therapeutic biomarker. Citation Format: Ophélia Maertens, Ryan Kuzmickas, Haley Manchester, Chloe Emerson, Alessandra Gavin, Caroline Guild, Terence Wong, Thomas De Raedt, Christian Bowman-Colin, Elodie Hatchi, Levi Garraway, Keith Flaherty, Shailja Pathania, Stephen Elledge, Karen Cichowski. MAPK pathway suppression unmasks latent DNA repair defects and confers a chemical synthetic vulnerability inBRAF,NRASandNF1-mutant melanomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-113.