Your browser doesn't support javascript.
loading
SIRT6 haploinsufficiency induces BRAFV600E melanoma cell resistance to MAPK inhibitors via IGF signalling.
Strub, Thomas; Ghiraldini, Flavia G; Carcamo, Saul; Li, Man; Wroblewska, Aleksandra; Singh, Rajendra; Goldberg, Matthew S; Hasson, Dan; Wang, Zichen; Gallagher, Stuart J; Hersey, Peter; Ma'ayan, Avi; Long, Georgina V; Scolyer, Richard A; Brown, Brian; Zheng, Bin; Bernstein, Emily.
Afiliação
  • Strub T; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
  • Ghiraldini FG; Department of Dermatology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
  • Carcamo S; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
  • Li M; Department of Dermatology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
  • Wroblewska A; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
  • Singh R; Department of Dermatology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
  • Goldberg MS; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
  • Hasson D; Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA.
  • Wang Z; 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.
  • Gallagher SJ; Department of Dermatology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
  • Hersey P; 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.
  • Ma'ayan A; Department of Dermatology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
  • Long GV; 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.
  • Scolyer RA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
  • Brown B; Department of Dermatology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
  • Zheng B; 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.
  • Bernstein E; Centenary Institute, Camperdown NSW 2050, The University of Sydney, Sydney, Australia.
Nat Commun ; 9(1): 3440, 2018 08 24.
Article em En | MEDLINE | ID: mdl-30143629
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptor IGF Tipo 1 / Sirtuínas / Proteínas Proto-Oncogênicas B-raf / Inibidores de Proteínas Quinases / Haploinsuficiência / Melanoma Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptor IGF Tipo 1 / Sirtuínas / Proteínas Proto-Oncogênicas B-raf / Inibidores de Proteínas Quinases / Haploinsuficiência / Melanoma Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2018 Tipo de documento: Article