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Nat Commun. 2018 Aug 24;9(1):3440. doi: 10.1038/s41467-018-05966-z.

SIRT6 haploinsufficiency induces BRAFV600E melanoma cell resistance to MAPK inhibitors via IGF signalling.

Author information

1
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
2
Department of Dermatology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
3
Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
4
Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA.
5
Department of Genetics and Genomic Sciences, Mount Sinai Center for Bioinformatics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
6
Department of Pathology, Mount Sinai Center for Bioinformatics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
7
Department of Pharmacological Sciences, Mount Sinai Center for Bioinformatics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
8
Centenary Institute, Camperdown NSW 2050, The University of Sydney, Sydney, Australia.
9
Melanoma Institute Australia, Wollstonecraft NSW 2065, The University of Sydney, Sydney, Australia.
10
Sydney Medical School, University of Sydney, Sydney, NSW, 2050, Australia.
11
Royal North Shore Hospital, Sydney, NSW, 2065, Australia.
12
Royal Prince Alfred Hospital, Sydney, NSW, 2050, Australia.
13
Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
14
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA. emily.bernstein@mssm.edu.
15
Department of Dermatology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA. emily.bernstein@mssm.edu.
16
Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA. emily.bernstein@mssm.edu.

Abstract

While multiple mechanisms of BRAFV600-mutant melanoma resistance to targeted MAPK signaling inhibitors (MAPKi) have been reported, the epigenetic regulation of this process remains undetermined. Here, using a CRISPR-Cas9 screen targeting chromatin regulators, we discover that haploinsufficiency of the histone deacetylase SIRT6 allows melanoma cell persistence in the presence of MAPKi. Haploinsufficiency, but not complete loss of SIRT6 promotes IGFBP2 expression via increased chromatin accessibility, H3K56 acetylation at the IGFBP2 locus, and consequent activation of the IGF-1 receptor (IGF-1R) and downstream AKT signaling. Combining a clinically applicable IGF-1Ri with BRAFi overcomes resistance of SIRT6 haploinsufficient melanoma cells in vitro and in vivo. Using matched melanoma samples derived from patients receiving dabrafenib + trametinib, we identify IGFBP2 as a potential biomarker for MAPKi resistance. Our study has not only identified an epigenetic mechanism of drug resistance, but also provides insights into a combinatorial therapy that may overcome resistance to standard-of-care therapy for BRAFV600-mutant melanoma patients.

PMID:
30143629
PMCID:
PMC6109055
DOI:
10.1038/s41467-018-05966-z
[Indexed for MEDLINE]
Free PMC Article

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