Loss of cohesin complex components STAG2 or STAG3 confers resistance to BRAF inhibition in melanoma

The protein kinase V-Raf murine sarcoma viral oncogene homolog B (BRAF) is an oncogenic driver and therapeutic target in melanoma. Inhibitors of BRAF (BRAFi) have shown high response rates and extended survival in melanoma patients bearing tumors that express BRAF Val600 mutations, but a vast majori...

Full description

Bibliographic Details
Main Authors:	Shen, Che-Hung, Kim, Sun Hye, Trousil, Sebastian, Frederick, Dennie T., Piris, Adriano, Yuan, Ping, Cai, Li, Gu, Lei, Li, Man, Lee, Jung Hyun, Mitra, Devarati, Fisher, David E., Sullivan, Ryan J., Flaherty, Keith T., Zheng, Bin
Format:	Online
Language:	English
Published:	2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5014622/

id	pubmed-5014622
recordtype	oai_dc
spelling	pubmed-50146222017-02-08 Loss of cohesin complex components STAG2 or STAG3 confers resistance to BRAF inhibition in melanoma Shen, Che-Hung Kim, Sun Hye Trousil, Sebastian Frederick, Dennie T. Piris, Adriano Yuan, Ping Cai, Li Gu, Lei Li, Man Lee, Jung Hyun Mitra, Devarati Fisher, David E. Sullivan, Ryan J. Flaherty, Keith T. Zheng, Bin Article The protein kinase V-Raf murine sarcoma viral oncogene homolog B (BRAF) is an oncogenic driver and therapeutic target in melanoma. Inhibitors of BRAF (BRAFi) have shown high response rates and extended survival in melanoma patients bearing tumors that express BRAF Val600 mutations, but a vast majority of these patients develop drug resistance. Here we show that loss of Stromal antigen 2 or 3 (STAG2 or STAG3), which encode subunits of the cohesin complex, in melanoma cells results in resistance to BRAFi. We identified loss-of-function mutations in STAG2 as well as decreased expression of STAG2 or STAG3 proteins in several tumor samples from patients with acquired resistance to BRAFi and in BRAFi-resistant melanoma cell lines. Knockdown of STAG2 or STAG3 decreased sensitivity of Val600Glu BRAF-mutant melanoma cells and xenograft tumors to BRAFi. Loss of STAG2 inhibited CCCTC-binding factor (CTCF)-mediated expression of dual specificity phosphatase 6 (DUSP6), leading to reactivation of ERK signaling. Our studies unveil a previously unknown genetic mechanism of BRAFi resistance and provide new insights into the tumor suppressor function of STAG2 and STAG3. 2016-08-08 2016-09 /pmc/articles/PMC5014622/ /pubmed/27500726 http://dx.doi.org/10.1038/nm.4155 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Shen, Che-Hung Kim, Sun Hye Trousil, Sebastian Frederick, Dennie T. Piris, Adriano Yuan, Ping Cai, Li Gu, Lei Li, Man Lee, Jung Hyun Mitra, Devarati Fisher, David E. Sullivan, Ryan J. Flaherty, Keith T. Zheng, Bin
spellingShingle	Shen, Che-Hung Kim, Sun Hye Trousil, Sebastian Frederick, Dennie T. Piris, Adriano Yuan, Ping Cai, Li Gu, Lei Li, Man Lee, Jung Hyun Mitra, Devarati Fisher, David E. Sullivan, Ryan J. Flaherty, Keith T. Zheng, Bin Loss of cohesin complex components STAG2 or STAG3 confers resistance to BRAF inhibition in melanoma
author_facet	Shen, Che-Hung Kim, Sun Hye Trousil, Sebastian Frederick, Dennie T. Piris, Adriano Yuan, Ping Cai, Li Gu, Lei Li, Man Lee, Jung Hyun Mitra, Devarati Fisher, David E. Sullivan, Ryan J. Flaherty, Keith T. Zheng, Bin
author_sort	Shen, Che-Hung
title	Loss of cohesin complex components STAG2 or STAG3 confers resistance to BRAF inhibition in melanoma
title_short	Loss of cohesin complex components STAG2 or STAG3 confers resistance to BRAF inhibition in melanoma
title_full	Loss of cohesin complex components STAG2 or STAG3 confers resistance to BRAF inhibition in melanoma
title_fullStr	Loss of cohesin complex components STAG2 or STAG3 confers resistance to BRAF inhibition in melanoma
title_full_unstemmed	Loss of cohesin complex components STAG2 or STAG3 confers resistance to BRAF inhibition in melanoma
title_sort	loss of cohesin complex components stag2 or stag3 confers resistance to braf inhibition in melanoma
description	The protein kinase V-Raf murine sarcoma viral oncogene homolog B (BRAF) is an oncogenic driver and therapeutic target in melanoma. Inhibitors of BRAF (BRAFi) have shown high response rates and extended survival in melanoma patients bearing tumors that express BRAF Val600 mutations, but a vast majority of these patients develop drug resistance. Here we show that loss of Stromal antigen 2 or 3 (STAG2 or STAG3), which encode subunits of the cohesin complex, in melanoma cells results in resistance to BRAFi. We identified loss-of-function mutations in STAG2 as well as decreased expression of STAG2 or STAG3 proteins in several tumor samples from patients with acquired resistance to BRAFi and in BRAFi-resistant melanoma cell lines. Knockdown of STAG2 or STAG3 decreased sensitivity of Val600Glu BRAF-mutant melanoma cells and xenograft tumors to BRAFi. Loss of STAG2 inhibited CCCTC-binding factor (CTCF)-mediated expression of dual specificity phosphatase 6 (DUSP6), leading to reactivation of ERK signaling. Our studies unveil a previously unknown genetic mechanism of BRAFi resistance and provide new insights into the tumor suppressor function of STAG2 and STAG3.
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5014622/
_version_	1613645603599810560

Loss of cohesin complex components STAG2 or STAG3 confers resistance to BRAF inhibition in melanoma

Similar Items