MAPK Pathway Suppression Unmasks Latent DNA Repair Defects and Confers a Chemical Synthetic Vulnerability in BRAF-, NRAS -, and NF1 -Mutant Melanomas
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Abstract
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 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, 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
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HDAC inhibitors have been considered for usage in combinatorial therapies for several cancers including melanoma.
“HDAC inhibitors have been considered for usage in combinatorial therapies for several cancers including melanoma47,65–67.”
From Epigenetic control of melanoma cell invasiveness by the stem cell factor SALL4 (2021) · cites this paper as [67]
BRAF/MEK inhibitors plus entinostat synergize to induce DNA damage and suppress DDR genes involved in HR and NHEJ.
“Interestingly, BRAF/MEK inhibitors in combination with entinostat (a preferred HDAC1/2/3 inhibitor) synergize to induce DNA damage and suppress expression of DDR genes involved in both HR and NHEJ (Maertens et al., 2019).”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Maertens et al., 2019
Depletion of HDAC3 (but not HDAC1/2 or 6) cooperates with BRAF/MEK inhibitors to kill melanoma cells.
“Depletion of HDAC3 (but not HDAC1/2 or 6) potently cooperates with these inhibitors to kill melanoma cells.”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Maertens et al., 2019
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- Authors
- Maertens, O., Kuzmickas, R., Manchester, H. E., Emerson, C. E., Gavin, A. G., Guild, C. J., Wong, T. C., De Raedt, T., Bowman-Colin, C., Hatchi, E., Garraway, L. A., Flaherty, K. T., Pathania, S., Elledge, S. J., & Cichowski, K.
- Affiliations
- Brigham and Women's Hospital (US)
- Broad Institute (US)
- 1Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
- Harvard University (US)
- University of Massachusetts Boston (US)
- ORCID
- Venue
- Cancer Discovery
- Published
- 2019-04-01
- Volume
- 9
- Issue
- 4
- Pages
- 526-545
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC10151004
- OpenAlex
- W2913242533
- Cited by
- 95
- References
- 45
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 18 · 2023: 14 · 2022: 10 · 2021: 17 · 2020: 17 · 2019: 5
- FWCI
- 4.05
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- HHS | NIH | National Cancer InstituteHHS | NIH | National Cancer Institute (NCI) (R01CA111754)
- Ludwig center at Harvard
- Children's Hospital Boston
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- melanoma, BRAF-mutant melanoma, NRAS-mutant melanoma, MAPK pathway inhibitors, entinostat, HDAC3 inhibition, DNA repair deficiency, MGMT expression, homologous recombination, non-homologous end joining, drug combination therapy, predictive biomarkers
- MeSH terms
- DNA Repair, Humans, Melanoma, Genes, ras, MAP Kinase Kinase Kinases, Proto-Oncogene Proteins B-raf
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