biostudies-literatureMaertens OChildren&apos;s Hospital BostonLudwig Center at HarvardLudwig center at HarvardHoward Hughes Medical InstituteNCI NIH HHSHHS | NIH | National Cancer InstituteHHS | NIH | National Cancer Institute (NCI)526-545https://www.ebi.ac.uk/biostudies/studies/S-EPMC10151004biostudies-literatureUnknown9(4)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, additCancer discoveryMAPK Pathway Suppression Unmasks Latent DNA Repair Defects and Confers a Chemical Synthetic Vulnerability in <i>BRAF-, NRAS</i>-, and <i>NF1</i>-Mutant Melanomas.PMC10151004R01CA111754R01 CA111754Gavin AGManchester HEKuzmickas RElledge SJHatchi EPathania SGuild CJFlaherty KTMaertens ODe Raedt TGarraway LAEmerson CEWong TCBowman-Colin CCichowski KfalseMAPK Pathway Suppression Unmasks Latent DNA Repair Defects and Confers a Chemical Synthetic Vulnerability in <i>BRAF-, NRAS</i>-, and <i>NF1</i>-Mutant Melanomas.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, addit2019-01-01T00:00:00Z2019 Apr2026-05-29T03:06:07.28Z2025-02-19T02:39:12.664ZS-EPMC101510043070980510.1158/2159-8290.cd-18-087910.1158/2159-8290.CD-18-0879