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Supplementary Figure S6 from Targeted Therapy of TERT-Rearranged Neuroblastoma with BET Bromodomain Inhibitor and Proteasome Inhibitor Combination Therapy

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posted on 2023-03-31, 22:32 authored by Jingwei Chen, Christopher Nelson, Matthew Wong, Andrew E. Tee, Pei Y. Liu, Ting La, Jamie I. Fletcher, Alvin Kamili, Chelsea Mayoh, Christoph Bartenhagen, Toby N. Trahair, Ning Xu, Nisitha Jayatilleke, Marie Wong, Hui Peng, Bernard Atmadibrata, Belamy B. Cheung, Qing Lan, Tracy M. Bryan, Pieter Mestdagh, Jo Vandesompele, Valerie Combaret, Valentina Boeva, Jenny Y. Wang, Isabelle Janoueix-Lerosey, Mark J. Cowley, Karen L. MacKenzie, Alla Dolnikov, Jinyan Li, Patsie Polly, Glenn M. Marshall, Roger R. Reddel, Murray D. Norris, Michelle Haber, Matthias Fischer, Xu D. Zhang, Hilda A. Pickett, Tao Liu

Supplementary Figure S6. OTX015 and carfilzomib exert synergistic anticancer effects partly by inducing oxidative stress and endoplasmic reticulum stress.

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ARC Foundation

Laboratory of Excellence

French Government

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ARTICLE ABSTRACT

TERT gene rearrangement with transcriptional superenhancers leads to TERT overexpression and neuroblastoma. No targeted therapy is available for clinical trials in patients with TERT-rearranged neuroblastoma. Anticancer agents exerting the best synergistic anticancer effects with BET bromodomain inhibitors were identified by screening an FDA-approved oncology drug library. The synergistic effects of the BET bromodomain inhibitor OTX015 and the proteasome inhibitor carfilzomib were examined by immunoblot and flow cytometry analysis. The anticancer efficacy of OTX015 and carfilzomib combination therapy was investigated in mice xenografted with TERT-rearranged neuroblastoma cell lines or patient-derived xenograft (PDX) tumor cells, and the role of TERT reduction in the anticancer efficacy was examined through rescue experiments in mice. The BET bromodomain protein BRD4 promoted TERT-rearranged neuroblastoma cell proliferation through upregulating TERT expression. Screening of an approved oncology drug library identified the proteasome inhibitor carfilzomib as the agent exerting the best synergistic anticancer effects with BET bromodomain inhibitors including OTX015. OTX015 and carfilzomib synergistically reduced TERT protein expression, induced endoplasmic reticulum stress, and induced TERT-rearranged neuroblastoma cell apoptosis which was blocked by TERT overexpression and endoplasmic reticulum stress antagonists. In mice xenografted with TERT-rearranged neuroblastoma cell lines or PDX tumor cells, OTX015 and carfilzomib synergistically blocked TERT expression, induced tumor cell apoptosis, suppressed tumor progression, and improved mouse survival, which was largely reversed by forced TERT overexpression. OTX015 and carfilzomib combination therapy is likely to be translated into the first clinical trial of a targeted therapy in patients with TERT-rearranged neuroblastoma.

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    Clinical Cancer Research

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    Drug TargetsOncoprotein & tumor suppressor drug targetsPediatric Cancers

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