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

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

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

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Citation: Shen, C., S. H. Kim, S. Trousil, D. T. Frederick, A. Piris, P. Yuan, L. Cai, et al. 2016. “Loss of cohesin complex components STAG2 or STAG3 confers resistance to BRAF inhibition in melanoma.” Nature medicine 22 (9): 1056-1061. doi:10.1038/nm.4155. http://dx.doi.org/10.1038/nm.4155.
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Abstract: 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.
Published Version: doi:10.1038/nm.4155
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5014622/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:31731818
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