Overcoming clinical resistance to EZH2 inhibition using rational epigenetic combination therapy Journal Article

   

Authors:	Kazansky, Y.; Cameron, D.; Mueller, H. S.; Demarest, P.; Zaffaroni, N.; Arrighetti, N.; Zuco, V.; Kuwahara, Y.; Somwar, R.; Ladanyi, M.; Qu, R.; de Stanchina, E.; Dela Cruz, F. S.; Kung, A. L.; Gounder, M. M.; Kentsis, A.
Article Title:	Overcoming clinical resistance to EZH2 inhibition using rational epigenetic combination therapy
Abstract:	Genetic mutations that promote resistance to the EZH2 inhibitor tazemetostat in SMARCB1-deficient epithelioid sarcomas and rhabdoid tumors were identified, and a combination therapy approach to counteract this resistance was proposed, potentially guiding future clinical trials. Epigenetic dependencies have become evident in many cancers. On the basis of antagonism between BAF/SWI-SNF and PRC2 in SMARCB1-deficient sarcomas, we recently completed the clinical trial of the EZH2 inhibitor tazemetostat. However, the principles of tumor response to epigenetic therapy in general, and tazemetostat in particular, remain unknown. Using functional genomics and diverse experimental models, we define molecular mechanisms of tazemetostat resistance in SMARCB1-deficient tumors. We found distinct acquired mutations that converge on the RB1/E2F axis and decouple EZH2-dependent differentiation and cell-cycle control. This allows tumor cells to escape tazemetostat-induced G1 arrest, suggests a general mechanism for effective therapy, and provides prospective biomarkers for therapy stratification, including PRICKLE1. On the basis of this, we develop a combination strategy to circumvent tazemetostat resistance using bypass targeting of AURKB. This offers a paradigm for rational epigenetic combination therapy suitable for translation to clinical trials for epithelioid sarcomas, rhabdoid tumors, and other epigenetically dysregulated cancers.Significance: 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. 897Significance: 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. 897Significance: 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
Keywords:	mutation; lymphoma; in-vitro; p53; reveals; growth; polycomb; aurora-b-kinase; cancer; ankrd11
Journal Title:	Cancer Discovery
Volume:	14
Issue:	6
ISSN:	2159-8274
Publisher:	American Association for Cancer Research
Date Published:	2024-06-01
Start Page:	965
End Page:	981
Language:	English
ACCESSION:	WOS:001239352000013
DOI:	10.1158/2159-8290.Cd-23-0110
PROVIDER:	wos
PMCID:	PMC11147720
PUBMED:	38315003
Notes:	Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Alex Kentsis -- Source: Wos

https://synapse.mskcc.org/synapse/works/has_related_data_chk/217107