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 (25686104)
Authors Bitler BG, Aird KM, Garipov A, Li H, Amatangelo M, Kossenkov AV, Schultz DC, Liu Q, Shih IeM, Conejo-Garcia JR, Speicher DW, Zhang R
Title Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers.
Journal Nature medicine
Vol 21
Issue 3
Date 2015 Mar
URL
Abstract Text The gene encoding ARID1A, a chromatin remodeler, shows one of the highest mutation rates across many cancer types. Notably, ARID1A is mutated in over 50% of ovarian clear cell carcinomas, which currently have no effective therapy. To date, clinically applicable targeted cancer therapy based on ARID1A mutational status has not been described. Here we show that inhibition of the EZH2 methyltransferase acts in a synthetic lethal manner in ARID1A-mutated ovarian cancer cells and that ARID1A mutational status correlated with response to the EZH2 inhibitor. We identified PIK3IP1 as a direct target of ARID1A and EZH2 that is upregulated by EZH2 inhibition and contributed to the observed synthetic lethality by inhibiting PI3K-AKT signaling. Importantly, EZH2 inhibition caused regression of ARID1A-mutated ovarian tumors in vivo. To our knowledge, this is the first data set to demonstrate a synthetic lethality between ARID1A mutation and EZH2 inhibition. Our data indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for cancers involving ARID1A mutations.

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
ARID1A R1446* EZH2 inhibitor
ARID1A Q449* EZH2 inhibitor
ARID1A Q528* EZH2 inhibitor
ARID1A Y551Tfs*68 EZH2 inhibitor
ARID1A V1561fs EZH2 inhibitor
ARID1A P224fs EZH2 inhibitor
ARID1A Q515* EZH2 inhibitor
ARID1A - MAST2 EZH2 inhibitor
ARID1A Q1334_R1335insQ EZH2 inhibitor
ARID1A D1838* EZH2 inhibitor
ARID1A S664* EZH2 inhibitor
ARID1A S1248* EZH2 inhibitor
ARID1A N2109Ffs*37 EZH2 inhibitor
ARID1A A1978Sfs*36 EZH2 inhibitor
ARID1A Q1741* EZH2 inhibitor
ARID1A Q920* EZH2 inhibitor
ARID1A S958Lfs*10 EZH2 inhibitor
ARID1A L2009_L2017del EZH2 inhibitor
ARID1A Q611Rfs*11 EZH2 inhibitor
ARID1A Q1409* EZH2 inhibitor
ARID1A Q393fs EZH2 inhibitor
ARID1A L1092* EZH2 inhibitor
ARID1A L657Pfs*81 EZH2 inhibitor
ARID1A Q1856* EZH2 inhibitor
ARID1A E1776* EZH2 inhibitor
ARID1A Q480* EZH2 inhibitor
ARID1A G276Efs*87 EZH2 inhibitor
ARID1A Q1519fs EZH2 inhibitor
ARID1A Q633* EZH2 inhibitor
ARID1A L2007del EZH2 inhibitor
ARID1A R1722* EZH2 inhibitor
ARID1A E992* EZH2 inhibitor
ARID1A S674fs EZH2 inhibitor
ARID1A R1528* EZH2 inhibitor
ARID1A R1721fs EZH2 inhibitor
ARID1A G319fs EZH2 inhibitor
ARID1A Q479* EZH2 inhibitor
ARID1A Q708* EZH2 inhibitor
ARID1A Q1631* EZH2 inhibitor
ARID1A E654Gfs*9 EZH2 inhibitor
ARID1A Q566* EZH2 inhibitor
ARID1A M1318fs EZH2 inhibitor
ARID1A Q403* EZH2 inhibitor
ARID1A Q1148* EZH2 inhibitor
ARID1A Q1131* EZH2 inhibitor
ARID1A R1721* EZH2 inhibitor
ARID1A W1670* EZH2 inhibitor
ARID1A loss EZH2 inhibitor
ARID1A Q1519Pfs*13 EZH2 inhibitor
ARID1A R1989* EZH2 inhibitor
ARID1A R693* EZH2 inhibitor
ARID1A H203fs EZH2 inhibitor
ARID1A Q199fs EZH2 inhibitor
ARID1A Q1493* EZH2 inhibitor
ARID1A Q790* EZH2 inhibitor
ARID1A P725fs EZH2 inhibitor
ARID1A W1545* EZH2 inhibitor
ARID1A P20_P21dup EZH2 inhibitor
ARID1A Q944* EZH2 inhibitor
ARID1A E1764* EZH2 inhibitor
ARID1A Q878* EZH2 inhibitor
ARID1A R750* EZH2 inhibitor
ARID1A E1596* EZH2 inhibitor
ARID1A Q543* EZH2 inhibitor
ARID1A S705fs EZH2 inhibitor
ARID1A K1071fs EZH2 inhibitor
ARID1A Q1172* EZH2 inhibitor
ARID1A R1276* EZH2 inhibitor
ARID1A G671Efs*71 EZH2 inhibitor
ARID1A A344_A348del EZH2 inhibitor
ARID1A S769* EZH2 inhibitor
ARID1A G1450fs EZH2 inhibitor
ARID1A R774Efs*55 EZH2 inhibitor
ARID1A Q1479* EZH2 inhibitor
ARID1A Y592* EZH2 inhibitor
ARID1A Q1342fs EZH2 inhibitor
ARID1A G276* EZH2 inhibitor
ARID1A Q1095* EZH2 inhibitor
ARID1A T294Pfs*69 EZH2 inhibitor
ARID1A negative EZH2 inhibitor
ARID1A S617* EZH2 inhibitor
ARID1A Q1894* EZH2 inhibitor
ARID1A Q546Rfs*73 EZH2 inhibitor
ARID1A Q372Afs*28 EZH2 inhibitor
ARID1A Q456* EZH2 inhibitor
ARID1A Q1584* EZH2 inhibitor
ARID1A inact mut EZH2 inhibitor
ARID1A G925* EZH2 inhibitor
ARID1A G1848fs EZH2 inhibitor
ARID1A E1780* EZH2 inhibitor
ARID1A Q1401* EZH2 inhibitor
ARID1A R727fs EZH2 inhibitor
ARID1A S11fs EZH2 inhibitor
ARID1A R1335* EZH2 inhibitor
ARID1A A1559* EZH2 inhibitor
ARID1A Q1212* EZH2 inhibitor
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
GSK126 GSK126 20 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
GSK126 GSK2816126|GSK-126 EZH2 inhibitor 18 GSK126 selectively inhibits EZH2, resulting in decreased H3K27 tri-methylation, and potentially leading to decreased tumor cell proliferation and reduced tumor growth (PMID: 23051747, PMID: 25686104).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ARID1A wild-type ovarian cancer no benefit GSK126 Preclinical - Cell culture Actionable In a preclinical study, GSK126 had no significant effect on the growth of ovarian cancer cells with wild-type ARID1A in culture (PMID: 25686104). 25686104
ARID1A mutant ovarian cancer sensitive GSK126 Preclinical - Cell line xenograft Actionable In a preclinical study, GSK126 selectively inhibited growth of ARID1A-mutant ovarian cancer cells in culture, and induced tumor regression in ARID1A-mutant ovarian cancer xenograft models (PMID: 25686104). 25686104
ARID1A dec exp ovarian cancer sensitive GSK126 Preclinical - Cell culture Actionable In a preclinical study, GSK126 inhibited growth of ovarian cancer cells with knockdown of ARID1A expression in culture (PMID: 25686104). 25686104
ARID1A mut PIK3CA act mut ovarian cancer sensitive GSK126 Preclinical - Cell culture Actionable In a preclinical study, expression of a constitutively active PIK3CA mutation in ARID1A-mutant ovarian cancer cell lines enhanced growth inhibition by GSK126 in culture (PMID: 25686104). 25686104
ARID1A mutant ovarian cancer sensitive UNC1999 Preclinical - Cell culture Actionable In a preclinical study, UNC1999 inhibited growth of ovarian cancer cell lines harboring ARID1A mutations in culture (PMID: 25686104). 25686104