2015
DOI: 10.1038/nm.3799
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Abstract: 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 has 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. ARID1A mutational status correlates with response to the … Show more

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Cited by 522 publications
(497 citation statements)
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References 40 publications
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“…Understanding epigenomic alterations and their genetic origin can identify new disease mechanisms (34), vulnerabilities (73,74), and therapeutic strategies (75)(76)(77). Through comprehensive profiling of histone modifications in primary normal-tumor pairs and cell lines, we generated a compendium of ccRCC-associated promoters and enhancers.…”
Section: Discussionmentioning
confidence: 99%
“…Understanding epigenomic alterations and their genetic origin can identify new disease mechanisms (34), vulnerabilities (73,74), and therapeutic strategies (75)(76)(77). Through comprehensive profiling of histone modifications in primary normal-tumor pairs and cell lines, we generated a compendium of ccRCC-associated promoters and enhancers.…”
Section: Discussionmentioning
confidence: 99%
“…TP53 and ARID1A are among potential sarcomatoid-specific targets for which therapeutics are in development (58,59). As drugs that mitigate effects of mutation in these genes enter clinical trials, their study in sarcomatoid renal tumors may be warranted.…”
Section: Discussionmentioning
confidence: 99%
“…Several lines of evidence suggest that EZH2 deregulation is an important driver of cancer development and progression and that inactivation of EZH2 may be therapeutically effective in many cancers [4,5,11,12,73,[76][77][78][79][80][81][82][83][84][85][86][87][88][89] . EZH2 is highly expressed in a wide range of cancer types, including lung, breast, colon, prostate, bladder and pancreatic cancer, as well as sarcomas and lymphomas [4,5,11,12,76,77,80,82,83,[85][86][87][88] .…”
Section: Prc2 and Diseasesmentioning
confidence: 99%
“…[105] . Bitlers et al reported that EZH2 inhibition by GSK126 acts in a synthetic lethal manner in ARID1A-mutated ovarian cancer cells and that ARID1A mutational status correlates with response to the EZH2 inhibitor [81] . Souroullaso et al reported an exquisite specific cooperation between activating genetic events of EZH2 and BRAF, which predicts synergistic activity for a combined therapy with RAF inhibitors and EZH2 inhibitors for B cell lymphomas and melanomas that harbor the oncogenic EZH2 Y641F mutation [78] .…”
Section: Drug Discovery Targeting Prc2mentioning
confidence: 99%