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

Publication ,  Journal Article
Bitler, BG; Aird, KM; Garipov, A; Li, H; Amatangelo, M; Kossenkov, AV; Schultz, DC; Liu, Q; Shih, I-M; Conejo-Garcia, JR; Speicher, DW; Zhang, R
Published in: Nat Med
March 2015

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.

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Published In

Nat Med

DOI

EISSN

1546-170X

Publication Date

March 2015

Volume

21

Issue

3

Start / End Page

231 / 238

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Up-Regulation
  • Transcription Factors
  • Signal Transduction
  • Pyridones
  • Proto-Oncogene Proteins c-akt
  • Polycomb Repressive Complex 2
  • Ovarian Neoplasms
  • Nuclear Proteins
  • Mutation
 

Citation

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Bitler, B. G., Aird, K. M., Garipov, A., Li, H., Amatangelo, M., Kossenkov, A. V., … Zhang, R. (2015). Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers. Nat Med, 21(3), 231–238. https://doi.org/10.1038/nm.3799
Bitler, Benjamin G., Katherine M. Aird, Azat Garipov, Hua Li, Michael Amatangelo, Andrew V. Kossenkov, David C. Schultz, et al. “Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers.Nat Med 21, no. 3 (March 2015): 231–38. https://doi.org/10.1038/nm.3799.
Bitler BG, Aird KM, Garipov A, Li H, Amatangelo M, Kossenkov AV, et al. Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers. Nat Med. 2015 Mar;21(3):231–8.
Bitler, Benjamin G., et al. “Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers.Nat Med, vol. 21, no. 3, Mar. 2015, pp. 231–38. Pubmed, doi:10.1038/nm.3799.
Bitler BG, Aird KM, Garipov A, Li H, Amatangelo M, Kossenkov AV, Schultz DC, Liu Q, Shih I-M, Conejo-Garcia JR, Speicher DW, Zhang R. Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers. Nat Med. 2015 Mar;21(3):231–238.

Published In

Nat Med

DOI

EISSN

1546-170X

Publication Date

March 2015

Volume

21

Issue

3

Start / End Page

231 / 238

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Up-Regulation
  • Transcription Factors
  • Signal Transduction
  • Pyridones
  • Proto-Oncogene Proteins c-akt
  • Polycomb Repressive Complex 2
  • Ovarian Neoplasms
  • Nuclear Proteins
  • Mutation