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SIRT6 haploinsufficiency induces BRAF V600E melanoma cell resistance to MAPK inhibitors via IGF signalling.
- Source :
-
Nature communications [Nat Commun] 2018 Aug 24; Vol. 9 (1), pp. 3440. Date of Electronic Publication: 2018 Aug 24. - Publication Year :
- 2018
-
Abstract
- While multiple mechanisms of BRAF <superscript>V600</superscript> -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 BRAF <superscript>V600</superscript> -mutant melanoma patients.
- Subjects :
- Animals
Apoptosis drug effects
Apoptosis genetics
Cell Line
Cell Proliferation drug effects
Cell Proliferation genetics
Chromatin Immunoprecipitation
DNA Damage drug effects
DNA Damage genetics
Female
Haploinsufficiency genetics
Humans
Melanoma genetics
Mice, Nude
Proto-Oncogene Proteins B-raf genetics
Receptor, IGF Type 1 genetics
Signal Transduction genetics
Signal Transduction physiology
Sirtuins genetics
Haploinsufficiency physiology
Melanoma drug therapy
Melanoma metabolism
Protein Kinase Inhibitors therapeutic use
Proto-Oncogene Proteins B-raf metabolism
Receptor, IGF Type 1 metabolism
Sirtuins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 9
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 30143629
- Full Text :
- https://doi.org/10.1038/s41467-018-05966-z