Data from MAPK Pathway Suppression Unmasks Latent DNA Repair Defects and Confers a Chemical Synthetic Vulnerability in <i>BRAF-, NRAS</i>-, and <i>NF1</i>-Mutant Melanomas

Abstract

<div>Abstract<p>Although the majority of <i>BRAF</i>-mutant melanomas respond to BRAF/MEK inhibitors, these agents are not typically curative. Moreover, they are largely ineffective in <i>NRAS</i>- and <i>NF1</i>-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 relatively resistant to these agents. Interestingly, <i>MGMT</i> 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.</p>Significance:<p>BRAF/MEK inhibitors are not typically curative in <i>BRAF</i>-mutant melanomas and are ineffective in <i>NRAS</i>- and <i>NF1</i>-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.</p><p><i>See related commentary by Lombard et al., p. 469</i>.</p><p><i>This article is highlighted in the In This Issue feature, p. 453</i></p></div>