Transcriptional Heterogeneity Overcomes Super-Enhancer Disrupting Drug Combinations in Multiple Myeloma

• Type of Material: Article
• Authors: Seth J. Welsh, Mayo Clinic; Benjamin Barwick, Emory University; Erin W. Meermeier, Mayo Clinic; Daniel L. Riggs, Mayo Clinic; Chang-Xin Shi, Mayo Clinic; Yuan Xiao Zhu, Mayo Clinic; Meaghen E. Sharik, Mayo Clinic; Megan T. Du, Mayo Clinic; Leslie D. Abrego Rocha, Mayo Clinic; Victoria M. Garbitt, Mayo Clinic; Caleb K. Stein, Mayo Clinic; Joachim L. Petit, Mayo Clinic; Nathalie Meurice, Mayo Clinic; Yuliza Tafoya Alvarado, Mayo Clinic; Rodrigo Fonseca, Mayo Clinic; Kennedi T. Todd, Mayo Clinic; Sochilt Brown, Mayo Clinic; Zachery J. Hammond, Mayo Clinic; Nicklus H. Cuc, Mayo Clinic; Courtney Wittenberg, Mayo Clinic; Camille Herzog, Mayo Clinic; Anna V. Roschke, National Cancer Institute; Yulia N. Demchenko, National Cancer Institute; Wei-dong D. Chen, National Cancer Institute; Peng Li, National Institute of Health; Wei Liao, National Institute of Health; Warren J. Leonard, National Institute of Health; Sagar Lonial, Emory University; Nizar J. Bahlis, Tom Baker Cancer Center; Paola Neri, Tom Baker Cancer Center; Lawrence Boise, Emory University; Marta Chesi, Mayo Clinic; P. Leif Bergsagel, Mayo Clinic
• Language: English
• Date: 2023-09-27
• Publisher: American Association for Cancer Research
• Publication Version: Final Published Version
• Copyright Statement: ©2023 The Authors; Published by the American Association for Cancer Research
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): https://doi.org/10.1158/2643-3230.BCD-23-0062
• Title of Journal or Parent Work: Blood Cancer Discovery
• Volume: 5
• Issue: 1
• Start Page: 34
• End Page: 55
• Grant/Funding Information: The publication costs of this article were defrayed in part by the payment of publication fees. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.; B.G. Barwick was supported by an ASH Scholar Award and NCI award 1K22CA266739. B.G. Barwick and L.H. Boise were supported by NCI award 3 R01 CA192844-04S1. B.G. Barwick, L.H. Boise, M. Chesi, and P.L. Bergsagel were supported by the Paula and Rodger Riney Foundation. B.G. Barwick, P. Neri, N.J. Bahlis, and L.H. Boise were supported by an MMRF Answer Fund Award. S.J. Welsh, M. Chesi, and P.L. Bergsagel were supported by a Cancer Moonshot U54 CA224018 and SPORE grant P50 CA186781.
• Keywords: Multiple myeloma (MM); super-enhancers; IMiD antimyeloma activity; IKZF3; malignancy; MYC; IRF4; IKZF1
• Research Categories: Health Sciences, Oncology

Abstract

Multiple myeloma (MM) is a malignancy that is often driven by MYC and that is sustained by IRF4, which are upregulated by super-enhancers. IKZF1 and IKZF3 bind to super-enhancers and can be degraded using immunomodulatory imide drugs (IMiD). Successful IMiD responses downregulate MYC and IRF4; however, this fails in IMiD-resistant cells. MYC and IRF4 downregulation can also be achieved in IMiD-resistant tumors using inhibitors of BET and EP300 transcriptional coactivator proteins; however, in vivo these drugs have a narrow therapeutic window. By combining IMiDs with EP300 inhibition, we demonstrate greater downregulation of MYC and IRF4, synergistic killing of myeloma in vitro and in vivo, and an increased therapeutic window. Interestingly, this potent combination failed where MYC and IRF4 expression was maintained by high levels of the AP-1 factor BATF. Our results identify an effective drug combination and a previously unrecognized mechanism of IMiD resistance. Significance: These results highlight the dependence of MM on IKZF1-bound super-enhancers, which can be effectively targeted by a potent therapeutic combination pairing IMiD-mediated degradation of IKZF1 and IKZF3 with EP300 inhibition. They also identify AP-1 factors as an unrecognized mechanism of IMiD resistance in MM.