Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers

Bitler, Benjamin G.; Aird, Katherine M.; Garipov, Azat; Li, Hua; Amatangelo, Michael; Kossenkov, Andrew V.; Schultz, D.; Liu, Qin; Shih, Ie Ming; Conejo-Garcia, José R.; Speicher, David W.; Zhang, Rugang

doi:10.1038/nm.3799

Cited by 572 publications

(553 citation statements)

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%

VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma

et al. 2017

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Protein-coding mutations in clear cell renal cell carcinoma (ccRCC) have been extensively characterized, frequently involving inactivation of the von Hippel-Lindau ( VHL ) tumor suppressor. Roles for noncoding cis -regulatory aberrations in ccRCC tumorigenesis, however, remain unclear. Analyzing 10 primary tumor/normal pairs and 9 cell lines across 79 chromatin profi les, we observed pervasive enhancer malfunction in ccRCC, with cognate enhancer-target genes associated with tissue-specifi c aspects of malignancy. Superenhancer profi ling identifi ed ZNF395 as a ccRCCspecifi c and VHL-regulated master regulator whose depletion causes near-complete tumor elimination in vitro and in vivo . VHL loss predominantly drives enhancer/superenhancer deregulation more so than promoters, with acquisition of active enhancer marks (H3K27ac, H3K4me1) near ccRCC hallmark genes. Mechanistically, VHL loss stabilizes HIF2α-HIF1β heterodimer binding at enhancers, subsequently recruiting histone acetyltransferase p300 without overtly affecting preexisting promoter-enhancer interactions. Subtype-specifi c driver mutations such as VHL may thus propagate unique pathogenic dependencies in ccRCC by modulating epigenomic landscapes and cancer gene expression. SIGnIFICAnCE:Comprehensive epigenomic profi ling of ccRCC establishes a compendium of somatically altered cis -regulatory elements, uncovering new potential targets including ZNF395, a ccRCC master regulator. Loss of VHL , a ccRCC signature event, causes pervasive enhancer malfunction, with binding of enhancer-centric HIF2α and recruitment of histone acetyltransferase p300 at preexisting lineage-specifi c promoter-enhancer complexes. Cancer Discov; 7(11); 1284-305.

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Section: Discussionmentioning

confidence: 99%

VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma

et al. 2017

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“…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%

Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma

Zhao

Said

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

104

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The presence of sarcomatoid features in clear cell renal cell carcinoma (ccRCC) confers a poor prognosis and is of unknown pathogenesis. We performed exome sequencing of matched normal-carcinomatous-sarcomatoid specimens from 21 subjects. Two tumors had hypermutation consistent with mismatch repair deficiency. In the remainder, sarcomatoid and carcinomatous elements shared 42% of somatic single-nucleotide variants (SSNVs). Sarcomatoid elements had a higher overall SSNV burden (mean 90 vs. 63 SSNVs, P = 4.0 × 10 −4 ), increased frequency of nonsynonymous SSNVs in PanCancer genes (mean 1.4 vs. 0.26, P = 0.002), and increased frequency of loss of heterozygosity (LOH) across the genome (median 913 vs. 460 Mb in LOH, P < 0.05), with significant recurrent LOH on chromosomes 1p, 9, 10, 14, 17p, 18, and 22. The most frequent SSNVs shared by carcinomatous and sarcomatoid elements were in known ccRCC genes including von Hippel-Lindau tumor suppressor (VHL), polybromo 1 (PBRM1), SET domain containing 2 (SETD2), phosphatase and tensin homolog (PTEN). Most interestingly, sarcomatoid elements acquired biallelic tumor protein p53 (TP53) mutations in 32% of tumors (P = 5.47 × 10 −17 ); TP53 mutations were absent in carcinomatous elements in nonhypermutated tumors and rare in previously studied ccRCCs. Mutations in known cancer drivers ATrich interaction domain 1A (ARID1A) and BRCA1 associated protein 1 (BAP1) were significantly mutated in sarcomatoid elements and were mutually exclusive with TP53 and each other. These findings provide evidence that sarcomatoid elements arise from dedifferentiation of carcinomatous ccRCCs and implicate specific genes in this process. These findings have implications for the treatment of patients with these poor-prognosis cancers.

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“…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%

Structure of the PRC2 complex and application to drug discovery

et al. 2017

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The polycomb repressive complexes 2 (PRC2) complex catalyzes tri-methylation of histone H3 lysine 27 (H3K27), a repressive chromatin marker associated with gene silencing. Overexpression and mutations of PRC2 are found in a wide variety of cancers, making the catalytic activity of PRC2 an important target of cancer therapy. This review highlights recent structural breakthroughs of the human PRC2 complex bound to the H3K27 peptide and a small molecule inhibitor, which provide critically needed insight into PRC2-targeted drug discovery.

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Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers

Cited by 572 publications

References 40 publications

VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma

VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma

Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma

Structure of the PRC2 complex and application to drug discovery

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