martes, 17 de febrero de 2015

Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers : Nature Medicine : Nature Publishing Group

Figure 1: GSK126, an EZH2 inhibitor, is selective against ARID1A-knockdown cells compared with controls.

(a) Flow diagram of the evaluation for a panel of epigenetic inhibitors. ECM, extracellular matrix. (b) Immunoblot of ARID1A, EZH2, H3K27Me3 and loading control β-actin in the indicated ARID1A wild-type RMG1 cells. (c) Quantification o…

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

Nature Medicine

(2015)

doi:10.1038/nm.3799

Received: 27 August 2014
Accepted: 05 January 2015
Published online: 16 February 2015

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 betweenARID1A mutation and EZH2 inhibition. Our data indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for cancers involving ARID1A mutations.