Overcoming Clinical Resistance to EZH2 Inhibition Using Rational Epigenetic Combination Therapy.

Yaniv Kazansky Daniel Cameron Helen S Mueller Phillip Demarest Nadia Zaffaroni Noemi Arrighetti Valentina Zuco Yasumichi Kuwahara Romel Somwar Marc Ladanyi Rui Qu Elisa De Stanchina Filemon Dela Cruz Andrew L Kung Mrinal M Gounder Alex Kentsis

Published in: Cancer discovery (2024)

Genomic studies of patient epithelioid sarcomas and rhabdoid tumors identify mutations converging on a common pathway for response to EZH2 inhibition. Resistance mutations decouple drug-induced differentiation from cell-cycle control. We identify an epigenetic combination strategy to overcome resistance and improve durability of response, supporting its investigation in clinical trials. See related commentary by Paolini and Souroullas, p. 903. This article is featured in Selected Articles from This Issue, p. 897.

Keyphrases

cell cycle
drug induced
combination therapy
liver injury
clinical trial
dna methylation
cell proliferation
gene expression
long non coding rna
long noncoding rna
randomized controlled trial
copy number
adverse drug
genome wide
study protocol
electronic health record