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.
Highlights
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
Proteomic, and epigenomic analyses, we discover that SIRTUIN 6 (SIRT6) haploinsufficiency increases IGFBP2 expression and promotes melanoma cell survival through the activation of IGF-1 receptor (IGF-1R)/AKT signaling
SKMel[239] cells stably expressing Cas[9] were infected with the singleguide RNA library (3–4 sgRNAs per gene encoded in pLKO.1-EGFP); GFP-positive cells were sorted for expansion (Fig. 1a) and cultured with DMSO, dabrafenib, or dabrafenib + trametinib for 6 weeks (Fig. 1a)
Summary
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. Recent reports have implicated DNA methylation, transcriptional changes, microRNA alterations, as well as microenvironmental stressors in promoting melanoma drug resistance to MAPKi in BRAFV600-mutant melanoma[24,25,26,27,28,29,30], suggesting non-genetic mechanisms of plasticity of melanoma tumors to overcome these therapies It suggests that epigenetic alterations may play a key role in rewiring the chromatin landscape of melanoma cells to allow adaptation to MAPKi. shedding light onto the transcriptomic and epigenetic alterations underlying acquired MAPKi resistance in melanoma is of critical importance. Our study provides information on: (1) a previously unknown epigenetic mechanism of melanoma drug resistance, (2) a dose-dependent effect of SIRT6 levels on the drug resistance phenotype, and (3) a combinatorial therapy that may overcome resistance to MAPKi for a subset of BRAFV600-mutant melanoma patients
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