Reference Detail

Contact

Missing content? – Request curation!

Request curation for specific Genes, variants, or PubMed publications.

Have questions, comments or suggestions? - Let us know!

Email us at : ckbsupport@jax.org

Ref Type Journal Article
PMID (27500726)
Authors Shen CH, Kim SH, Trousil S, Frederick DT, Piris A, Yuan P, Cai L, Gu L, Li M, Lee JH, Mitra D, Fisher DE, Sullivan RJ, Flaherty KT, Zheng B
Title Loss of cohesin complex components STAG2 or STAG3 confers resistance to BRAF inhibition in melanoma.
Journal Nature medicine
Vol 22
Issue 9
Date 2016 Sep
URL
Abstract Text 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.

Filtering

  • Case insensitive filtering will display rows where any text in any cell matches the filter term
  • Simple literal full or partial string matches
  • Separate multiple filter terms with a spaces, order doesn't matter (a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page, filtering has no impact on query parameters
  • Use quotes to match a longer phrase which contains spaces "mtor c1483f"

Sorting

  • Generally, the default sort order for tables is set to be first column ascending, however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column, be sure to set ascending or descending order for a given column, before moving on to the next column.

Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
STAG2 D193N missense loss of function STAG2 D193N does not lie within any known functional domains of the Stag2 protein (UniProt.org). D193N confers a loss of function to the Stag2 protein as demonstrated by decreased binding to Rad21 and Smc1a, and loss of Ctcf binding to the DUSP6 promoter region, leading to decreased Dusp6 expression and increased levels of phosphorylated Erk in cultured cells (PMID: 27500726), and is associated with acquired resistance to BRAF inhibitors (PMID: 27500726). Y
STAG2 K1083* nonsense loss of function STAG2 K1083* results in a premature truncation of the Stag2 protein at amino acid 1083 of 1231 (UniProt.org). K1083* is associated with decreased Stag2 protein expression in patient cells, results in decreased Ctcf binding to DUSP6 promoter region and decreased Dusp6 expression in cultured cells (PMID: 27500726), and is associated with acquired resistance to BRAF inhibitors (PMID: 27500726). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E STAG2 D193N melanoma resistant Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, Zelboraf (vemurafenib) failed to inhibit colony formation and reduce Erk activation in a melanoma cell line harboring BRAF V600E that was found to have acquired a STAG2 D193N mutation in culture (PMID: 27500726). 27500726
BRAF mut STAG2 dec exp melanoma decreased response Vemurafenib Preclinical - Cell line xenograft Actionable In a preclinical study, decreasing Stag2 expression level through shRNA knockdown in BRAF mutated melanoma cell lines resulted in decreased response to Zelboraf (vemurafenib) both in culture and in cell line xenograft models (PMID: 27500726). 27500726
BRAF V600E STAG2 K1083* melanoma resistant Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, Zelboraf (vemurafenib) failed to inhibit colony formation and reduce Erk activation in a melanoma cell line harboring BRAF V600E that was found to have acquired a STAG2 K1083* mutation in culture (PMID: 27500726). 27500726
BRAF mut STAG2 dec exp melanoma decreased response Dabrafenib Preclinical - Cell culture Actionable In a preclinical study, decreasing Stag2 expression level through shRNA knockdown in BRAF mutated melanoma cell lines resulted in decreased response to Tafinlar (dabrafenib) in culture (PMID: 27500726). 27500726
BRAF mut STAG2 dec exp melanoma decreased response Dabrafenib + Trametinib Preclinical - Cell culture Actionable In a preclinical study, decreasing Stag2 expression level through shRNA knockdown in BRAF mutated melanoma cells resulted in decreased response to Mekinist (trametinib) and Tafinlar (dabrafenib) combination treatment in culture (PMID: 27500726). 27500726
BRAF mut STAG2 dec exp melanoma decreased response Trametinib Preclinical - Cell culture Actionable In a preclinical study, decreasing Stag2 expression level through shRNA knockdown in BRAF mutated melanoma cells resulted in decreased response to Mekinist (trametinib) in culture (PMID: 27500726). 27500726
NRAS mut STAG2 dec exp melanoma decreased response Trametinib Preclinical - Cell culture Actionable In a preclinical study, decreasing Stag2 expression level through shRNA knockdown in NRAS mutated melanoma cell lines resulted in decreased response to Mekinist (trametinib) in culture (PMID: 27500726). 27500726