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

Thomas Strub, Flavia G. Ghiraldini, Saul Carcamo, Man Li, Aleksandra Wroblewska, Rajendra Singh, Matthew S. Goldberg, Dan Hasson, Zichen Wang, Stuart J. Gallagher, Peter Hersey, Avi Ma’ayan, Georgina V. Long, Richard A. Scolyer, Brian Brown, Bin Zheng and Emily Bernstein ()
Additional contact information
Thomas Strub: Icahn School of Medicine at Mount Sinai
Flavia G. Ghiraldini: Icahn School of Medicine at Mount Sinai
Saul Carcamo: Icahn School of Medicine at Mount Sinai
Man Li: Harvard Medical School
Aleksandra Wroblewska: Icahn School of Medicine at Mount Sinai
Rajendra Singh: Icahn School of Medicine at Mount Sinai
Matthew S. Goldberg: Icahn School of Medicine at Mount Sinai
Dan Hasson: Icahn School of Medicine at Mount Sinai
Zichen Wang: Icahn School of Medicine at Mount Sinai
Stuart J. Gallagher: The University of Sydney
Peter Hersey: The University of Sydney
Avi Ma’ayan: Icahn School of Medicine at Mount Sinai
Georgina V. Long: The University of Sydney
Richard A. Scolyer: The University of Sydney
Brian Brown: Icahn School of Medicine at Mount Sinai
Bin Zheng: The University of Sydney
Emily Bernstein: Icahn School of Medicine at Mount Sinai

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05966-z

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