Page 161 - Haematologica Vol. 110 - January 2025

ARTICLE - Plasma Cell DIsorders
Unlocking the therapeutic potential of selective CDK7 and
BRD4 inhibition against multiple myeloma cell growth
Yao Yao,1-3 Shuhui Deng,1,4 Jessica Fong Ng,1 Mei Yuan,2 Chandraditya Chakraborty,1 Vera Joy Weiler,1 Nikhil Munshi1,5 and Mariateresa Fulciniti1
1Jerome Lipper Multiple Myeloma Disease Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; 2Blood Disease Institute, Key Laboratory of Bone Marrow Stem Cell, Xuzhou Medical University, Xuzhou, China; 3The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; 4State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China and 5VA Boston Healthcare System, Boston, MA, USA
Abstract
Multiple myeloma (MM) is a plasma cell malignancy that is considered incurable despite the recent therapeutic advances. Effective targeted therapies are, therefore, needed. Our previous studies proved that inhibiting CDK7 impairs the cell cycle and metabolic programs by disrupting E2F1 and MYC transcriptional activities, making it an appealing therapeutic target for MM. Given that CDK7 and BRD4 operate in two distinct regulatory axes in MM, we hypothesized that targeting these two complementary pathways simultaneously would lead to a deeper and more durable response. Indeed, combination therapy had superior activity against MM cell growth and viability, and induced apoptosis to a greater extent than did single-agent therapy in both cell lines and patients’ cells. This synergistic activity was also observed in Waldenström macroglobulinemia (WM) cells and with other inhibitors of E2F1 activity. Dual inhibition effectively impaired the MYC and E2F transcriptional programs and MM tumor growth and progression in xenograft animal models, providing evidence for the potential of com- bination therapy as a therapeutic strategy in MM and WM.
Introduction
Multiple myeloma (MM) is characterized by aberrant cell cycle regulation and enhancer alterations.1 Dysregulation of the cyclin-dependent kinase (CDK)–retinoblastoma (RB)– early 2 factor (E2F) axis, which is the core transcriptional machinery controlling cell cycle progression and timing and fidelity of genome replication, is universally observed, fos- tering uncontrolled malignant cell proliferation.2-4 Additionally, besides cell cycle regulators, transcription factors, chromatin-associated factors that mark DNA and histone proteins with heritable, chemical modifications and other essential components of the transcriptional apparatus, are frequently disrupted in MM, manifesting as a notable dependency, as indicated by meta-analyses of pan-cancer genome-wide CRISPR screening data.5
Bromodomains are protein interaction modules that spe- cifically recognize ε-N-lysine acetylation motifs functioning as “readers” of the lysine acetylation state.6 Dysfunction of bromodomain proteins has been linked to the development of several diseases, including cancer.7 Bromodomain-con-
taining protein 4 (BRD4) is a member of the bromodomain and extraterminal (BET) family of proteins characterized by two N-terminal bromodomains and an extraterminal (ET) domain, which is involved in many processes including tran- scription elongation and activation of genes involved in cell growth and cell cycle progression.8 Many studies have been focused on the role of BRD4 in cancer, and BET inhibitors have shown significant activity against various types of tu- mors.8 BRD4 positively correlates with disease progression in MM patients and MM cells are sensitive to treatment with the prototypic BRD4 inhibitor JQ1, which causes preferential loss of transcription at super-enhancer-associated genes and induces cell cycle arrest and a senescent phenotype.9 Other BET bromodomain inhibitors showed significant efficacy in preclinical MM models.9-12
However, the emergence of intrinsic and acquired resistance to BRD4 inhibitors as well as their unwanted toxicities and side effects hampered their widespread clinical application.13,14 These problems may potentially be overcome by combining BRD4 inhibitors with complementary therapies, enabling lower doses of BRD4 inhibitors and enhancing treatment specificity.15
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Correspondence: M. Fulciniti mariateresa_fulciniti@dfci.harvard.edu
Received: Accepted: Early view:
March 31, 2024. July 15, 2024. July 25, 2024.
https://doi.org/10.3324/haematol.2024.285491
©2025 Ferrata Storti Foundation Published under a CC BY-NC license