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MAPK pathway suppression unmasks latent DNA repair defects and confers a chemical synthetic vulnerability in BRAF, NRAS, and NF1 mutant melanomas

Ophelia Maertens, Ryan Kuzmickas, Haley E Manchester, Chloe E. Emerson, Alessandra G Gavin, Caroline J Guild, Terence C Wong, Thomas De Raedt, Christian Bowman-Colin, Elodie Hatchi, Levi A. Garraway, Keith T Flaherty (+3 others)
2019 Cancer Discovery  

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Although 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, in both models that are sensitive or
more » ... tively 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, addition of entinostat triggers the concomitant suppression of nonhomologous end-joining 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. SIGNIFICANCE: BRAF/MEK inhibitors are not typically curative in BRAF-mutant melanomas and are ineffective in NRAS- and NF1-mutant tumors. We show that HDAC inhibitors dramatically enhance the efficacy of BRAF/MEK inhibitors in sensitive and insensitive RAS pathway-driven melanomas by coordinately suppressing two DNA repair pathways, and identify a clinical biomarker that predicts responsiveness.See related commentary by Lombard et al., p. 469.This article is highlighted in the In This Issue feature, p. 453.
doi:10.1158/2159-8290.cd-18-0879 pmid:30709805 fatcat:6dgkcb5jazb5rjgjeg75mns5ci
Citation

Ophelia Maertens, Ryan Kuzmickas, Haley E Manchester, Chloe E. Emerson, Alessandra G Gavin, Caroline J Guild, Terence C Wong, Thomas De Raedt, Christian Bowman-Colin, Elodie Hatchi, Levi A. Garraway, Keith T Flaherty, Shailja Pathania, Stephen J. Elledge, Karen Cichowski. "MAPK pathway suppression unmasks latent DNA repair defects and confers a chemical synthetic vulnerability in BRAF, NRAS, and NF1 mutant melanomas." Cancer Discovery 9.4 (2019) CD-18-0879