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

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; howev...

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Published in:	Blood cancer discovery Vol. 5; no. 1; pp. 34 - 55
Main Authors:	Welsh, Seth J, Barwick, Benjamin G, Meermeier, Erin W, Riggs, Daniel L, Shi, Chang-Xin, Zhu, Yuan Xiao, Sharik, Meaghen E, Du, Megan T, Abrego Rocha, Leslie D, Garbitt, Victoria M, Stein, Caleb K, Petit, Joachim L, Meurice, Nathalie, Tafoya Alvarado, Yuliza, Fonseca, Rodrigo, Todd, Kennedi T, Brown, Sochilt, Hammond, Zachery J, Cuc, Nicklus H, Wittenberg, Courtney, Herzog, Camille, Roschke, Anna V, Demchenko, Yulia N, Chen, Wei-Dong D, Li, Peng, Liao, Wei, Leonard, Warren J, Lonial, Sagar, Bahlis, Nizar J, Neri, Paola, Boise, Lawrence H, Chesi, Marta, Bergsagel, P Leif
Format:	Journal Article
Language:	English
Published:	United States American Association for Cancer Research 08-01-2024
Subjects:	Drug Combinations Drug Resistance Gene Regulation Hematological Cancers Humans Immunomodulating Agents Lenalidomide - pharmacology Lenalidomide - therapeutic use Multiple Myeloma - drug therapy Multiple Myeloma - genetics Transcription Factor AP-1 - therapeutic use Tumor Heterogeneity
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Summary:	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. 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. See related article by Neri, Barwick, et al., p. 56. See related commentary by Yun and Cleveland, p. 5. This article is featured in Selected Articles from This Issue, p. 4.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 S.J. Welsh and B.G. Barwick contributed equally to this article. Blood Cancer Discov 2024;5:34–55
ISSN:	2643-3230 2643-3249 2643-3249
DOI:	10.1158/2643-3230.BCD-23-0062