Epigenetic targeting of PGBD5-dependent DNA damage in SMARCB1-deficient sarcomas
Yaniv Kazansky, Helen S. Mueller, Daniel Cameron, Phillip Demarest, Nadia Zaffaroni, Noemi Arrighetti, Valentina Zuco, Prabhjot S. Mundi, Yasumichi Kuwahara, Romel Somwar, Rui Qu, Andrea Califano, Elisa de Stanchina, Filemon S. Dela Cruz, Andrew L. Kung, Mrinal M. Gounder, Alex Kentsis
Yaniv Kazansky, Helen S. Mueller, Daniel Cameron, Phillip Demarest, Nadia Zaffaroni, Noemi Arrighetti, Valentina Zuco, Prabhjot S. Mundi, Yasumichi Kuwahara, Romel Somwar, Rui Qu, Andrea Califano, Elisa de Stanchina, Filemon S. Dela Cruz, Andrew L. Kung, Mrinal M. Gounder, Alex Kentsis
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Research Article Cell biology Oncology

Epigenetic targeting of PGBD5-dependent DNA damage in SMARCB1-deficient sarcomas

Abstract

Despite the potential of targeted epigenetic therapies, most cancers do not respond to current epigenetic drugs. The polycomb repressive complex EZH2 inhibitor tazemetostat was recently approved for the treatment of SMARCB1-deficient epithelioid sarcomas, based on the functional antagonism between PRC2 and SMARCB1. Through the analysis of tumors of patients treated with tazemetostat, we recently defined key principles of their response and resistance to EZH2 epigenetic therapy. Here, using transcriptomic inference from SMARCB1-deficient tumor cells, we nominate the DNA damage repair kinase ATR as a target for rational EZH2 combination epigenetic therapy. We showed that EZH2 inhibition promotes DNA damage in epithelioid and rhabdoid tumor cells, at least in part via its induction of piggyBac transposable element derived 5 (PGBD5). We leveraged this collateral synthetic lethal dependency to target PGBD5-dependent DNA damage by inhibition of ATR, but not CHK1, using the ATR inhibitor elimusertib. Consequently, combined EZH2 and ATR inhibition improved therapeutic responses in diverse patient-derived epithelioid and rhabdoid tumors in vivo. This advances a combination epigenetic therapy based on EZH2-PGBD5 synthetic lethal dependency suitable for immediate translation to clinical trials for patients.

Authors

Yaniv Kazansky, Helen S. Mueller, Daniel Cameron, Phillip Demarest, Nadia Zaffaroni, Noemi Arrighetti, Valentina Zuco, Prabhjot S. Mundi, Yasumichi Kuwahara, Romel Somwar, Rui Qu, Andrea Califano, Elisa de Stanchina, Filemon S. Dela Cruz, Andrew L. Kung, Mrinal M. Gounder, Alex Kentsis

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Figure 1

ATR inhibition is a therapeutic target and shows activity in tazemetostat-resistant rhabdoid tumor cells.

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ATR inhibition is a therapeutic target and shows activity in tazemetosta...
(A and B) metaVIPER analysis of rhabdoid tumor transcriptomes for proteins within the OncoTarget protein set (A) and the complete metaVIPER protein set (B). (C) Inhibitors rank ordered by IC50, data from Lee, et al. (D) DESeq2-normalized read counts of cells treated with 10 μM tazemetostat (TAZ) versus equivalent volume of DMSO for 11 days. n = 3 biological replicates per condition. ***P < 0.001; P = 1.2 × 10–7, 1.3 × 10–6, 1.6 × 10–6, and for RB1WT, RB1del E1, and RB1del F2, respectively, by 2-sided Student’s t test. (E) Volcano plot of previously published RNA-Seq data from cells treated with 10 μM TAZ vs. equivalent volume of DMSO for 11 days. n = 3 replicates per condition. Dots in red indicate genes with log2(expression fold-change) > ±1 and P < 0.01. (F) G401 cells treated with elimusertib for 4 days (experiment was repeated 3 times; representative is shown here).