title: Loss of cohesin complex components STAG2 or STAG3 confers resistance to BRAF inhibition in melanoma.
abstract: The protein kinase B-Raf proto-oncogene, serine/threonine kinase (BRAF) is an oncogenic driver and therapeutic target in melanoma. Inhibitors of BRAF (BRAFi) have shown high response rates and extended survival in patients with melanoma who bear tumors that express mutations encoding BRAF proteins mutant at Val600, but a vast majority of these patients develop drug resistance. Here we show that loss of stromal antigen 2 (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 expression decreased sensitivity of BRAF(Val600Glu)-mutant melanoma cells and xenograft tumors to BRAFi. Loss of STAG2 inhibited CCCTC-binding-factor-mediated expression of dual specificity phosphatase 6 (DUSP6), leading to reactivation of mitogen-activated protein kinase (MAPK) signaling (via the MAPKs ERK1 and ERK2; hereafter referred to as ERK). Our studies unveil a previously unknown genetic mechanism of BRAFi resistance and provide new insights into the tumor suppressor function of STAG2 and STAG3.
authors: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
authors: Che-Hung
authors: CH
authors: Shen
authors: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
authors: Sun Hye
authors: SH
authors: Kim
authors: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
authors: Sebastian
authors: S
authors: Trousil
authors: Department of Medical Oncology, Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
authors: Dennie T
authors: DT
authors: Frederick
authors: Department of Dermatology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors: Adriano
authors: A
authors: Piris
authors: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
authors: Ping
authors: P
authors: Yuan
authors: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
authors: Li
authors: L
authors: Cai
authors: Division of Newborn Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors: Lei
authors: L
authors: Gu
authors: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
authors: Man
authors: M
authors: Li
authors: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
authors: Jung Hyun
authors: JH
authors: Lee
authors: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
authors: Devarati
authors: D
authors: Mitra
authors: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.|Department of Medical Oncology, Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
authors: David E
authors: DE
authors: Fisher
authors: Department of Medical Oncology, Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
authors: Ryan J
authors: RJ
authors: Sullivan
authors: Department of Medical Oncology, Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
authors: Keith T
authors: KT
authors: Flaherty
authors: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
authors: Bin
authors: B
authors: Zheng
mesh_terms: D034961:Antigens, Nuclear / Q000235:genetics*; D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D054642:Dual Specificity Phosphatase 6 / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000627:therapeutic use*; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D000090063:Proto-Oncogene Mas; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors; D012097:Repressor Proteins / Q000378:metabolism; D013449:Sulfonamides / Q000627:therapeutic use*; D000077484:Vemurafenib; D000097722:Cohesins
chemical_list: D034961:Antigens, Nuclear; D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D054642:Dual Specificity Phosphatase 6; D007211:Indoles; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D048493:Proto-Oncogene Proteins B-raf; D012097:Repressor Proteins; D013449:Sulfonamides; D000077484:Vemurafenib; D000097722:Cohesins; C000619697:CTCF protein, human; C000715470:MAS1 protein, human; C508565:STAG2 protein, human; C406153:STAG3 protein, human; C482119:BRAF protein, human; C517035:DUSP6 protein, human