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

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

Research output: Contribution to journalArticle

263 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)231-238
Number of pages8
JournalNature Medicine
Volume21
Issue number3
DOIs
StatePublished - Jan 1 2015

Fingerprint

Methyltransferases
Cells
Gene encoding
Phosphatidylinositol 3-Kinases
Chromatin
Tumors
Neoplasms
Mutation
Mutation Rate
Ovarian Neoplasms
Pharmacology
Carcinoma
Synthetic Lethal Mutations
Therapeutics
Genes

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Bitler, B. G., Aird, K., Garipov, A., Li, H., Amatangelo, M., Kossenkov, A. V., ... Zhang, R. (2015). Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers. Nature Medicine, 21(3), 231-238. https://doi.org/10.1038/nm.3799
Bitler, Benjamin G. ; Aird, Katherine ; Garipov, Azat ; Li, Hua ; Amatangelo, Michael ; Kossenkov, Andrew V. ; Schultz, David C. ; Liu, Qin ; Shih, Ie Ming ; Conejo-Garcia, Jose R. ; Speicher, David W. ; Zhang, Rugang. / Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers. In: Nature Medicine. 2015 ; Vol. 21, No. 3. pp. 231-238.
@article{f3da8a9d8a8f481b8ddf885d37f77444,
title = "Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers",
abstract = "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.",
author = "Bitler, {Benjamin G.} and Katherine Aird and Azat Garipov and Hua Li and Michael Amatangelo and Kossenkov, {Andrew V.} and Schultz, {David C.} and Qin Liu and Shih, {Ie Ming} and Conejo-Garcia, {Jose R.} and Speicher, {David W.} and Rugang Zhang",
year = "2015",
month = "1",
day = "1",
doi = "10.1038/nm.3799",
language = "English (US)",
volume = "21",
pages = "231--238",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "3",

}

Bitler, BG, Aird, K, Garipov, A, Li, H, Amatangelo, M, Kossenkov, AV, Schultz, DC, Liu, Q, Shih, IM, Conejo-Garcia, JR, Speicher, DW & Zhang, R 2015, 'Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers', Nature Medicine, vol. 21, no. 3, pp. 231-238. https://doi.org/10.1038/nm.3799

Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers. / Bitler, Benjamin G.; Aird, Katherine; Garipov, Azat; Li, Hua; Amatangelo, Michael; Kossenkov, Andrew V.; Schultz, David C.; Liu, Qin; Shih, Ie Ming; Conejo-Garcia, Jose R.; Speicher, David W.; Zhang, Rugang.

In: Nature Medicine, Vol. 21, No. 3, 01.01.2015, p. 231-238.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers

AU - Bitler, Benjamin G.

AU - Aird, Katherine

AU - Garipov, Azat

AU - Li, Hua

AU - Amatangelo, Michael

AU - Kossenkov, Andrew V.

AU - Schultz, David C.

AU - Liu, Qin

AU - Shih, Ie Ming

AU - Conejo-Garcia, Jose R.

AU - Speicher, David W.

AU - Zhang, Rugang

PY - 2015/1/1

Y1 - 2015/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84925502851&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84925502851&partnerID=8YFLogxK

U2 - 10.1038/nm.3799

DO - 10.1038/nm.3799

M3 - Article

C2 - 25686104

AN - SCOPUS:84925502851

VL - 21

SP - 231

EP - 238

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

IS - 3

ER -