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

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

Full text not available from this repository.
Item Type: Article
Status: Published
Official URL: https://doi.org/10.1038/s41467-018-05966-z
Journal or Publication Title: Nature Communications
Volume: 9
Number: 1
Date: 2018
Divisions: Melanoma Oncology and Immunology
Depositing User: General Admin
Identification Number: 10.1038/s41467-018-05966-z
ISSN: 2041-1723
Date Deposited: 03 Jan 2021 22:46
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.

Creators:
Creators
Email
Strub, Thomas
UNSPECIFIED
Ghiraldini, Flavia G.
UNSPECIFIED
Carcamo, Saul
UNSPECIFIED
Li, Man
UNSPECIFIED
Wroblewska, Aleksandra
UNSPECIFIED
Singh, Rajendra
UNSPECIFIED
Goldberg, Matthew S.
UNSPECIFIED
Hasson, Dan
UNSPECIFIED
Wang, Zichen
UNSPECIFIED
Gallagher, Stuart J.
UNSPECIFIED
Hersey, Peter
UNSPECIFIED
Ma’ayan, Avi
UNSPECIFIED
Long, Georgina V.
UNSPECIFIED
Scolyer, Richard A.
UNSPECIFIED
Brown, Brian
UNSPECIFIED
Zheng, Bin
UNSPECIFIED
Bernstein, Emily
UNSPECIFIED
Last Modified: 03 Jan 2021 22:46
URI: https://eprints.centenary.org.au/id/eprint/525

Actions (login required)

View Item View Item