VCU Institute of Molecular Medicine (VIMM) NEWS & VIEWS
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The VIMM, established in 2008 by Paul B. Fisher, MPh, PhD, FNAI, the Founding Director, is comprised of outstanding scientists/clinicians from VCU School of Medicine and external affiliate members focusing on important medical-related research in cancer, neurodegeneration and infectious diseases. The purpose of this NEWS & VIEWS is to highlight the exciting research being performed by VIMM members.
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VIMM scientist reports that the Covalent CDK7 Inhibitor THZ1 Potently Induces Apoptosis in Multiple Myeloma Cells
In Vitro
and
In Vivo
- CDK7 is a component of the TFIIH (general transcription factor IIH) multiprotein complex which regulates transcription. Interference with CDK7 disrupts the p-TEFb transcription complex/RNA Pol II and leads to inhibition of transcription and down-regulation of multiple short-lived proteins. Pharmacologic agents that disrupt CDK7 inhibit cell cycle progression in multiple myeloma (MM) cells.
- THZ1 is a covalent inhibitor of CDK7 that triggers down-regulation of several genes involved in cell cycle progression and survival in myeloma cells e.g., BCL-xL, MCL-1, and c-Myc.
- Treatment of MM cells with THZ1 inhibited growth and induced cell death in MM cells, while sharply increasing the lethal effects of multiple anti-myeloma agents, e.g., bortezomib, carfilzomib, and the BCL-2 antagonist venetoclax.
- Analogous results were obtained when CDK7 was knocked out by CRISPR-Cas technology in MM cells.
- THZ1 displayed similar activity against primary patient-derived MM cells and their primitive progenitors. THZ1 significantly inhibited tumor growth and prolonged survival in a human xenograft MM model.
- Collectively, these findings argue that CDK7 inhibitors, either alone or in rational combination strategies, warrant attention in MM therapy.
Multiple myeloma is a disease of accumulation of mature plasma cells that despite recent advances, generally remains incurable, prompting the search for novel and more effective therapeutic strategies. CDK7 is a component of the TFIIH (general transcription factor IIH) multiprotein complex that cooperates with pTEFb (translation elongation factor b) to regulate RNA Pol II transcriptional activity. Because there is aberrant transcription in most cancers, including multiple myeloma, CDK7 has become the focus of attention for therapeutic targeting. This has led to the development of the covalent CDK7 inhibitor THZ1, which has activity in several c-Myc-driven tumor types in pre-clinical studies, including neuroblastoma, breast
cancer, and small cell lung cancer. Moreover, several CDK7 inhibitors have recently entered the clinical arena.
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In
light of the observation that c-Myc plays an important role in multiple myeloma cell survival and proliferation,
the Grant laboratory
sought to determine whether CDK7 inhibition might represent a viable option in this disease. They found that THZ effectively induces cell death in diverse human myeloma cell models, including those resistant to conventional agents such as proteasome inhibitors (
Figure 1
). These events were associated with multiple perturbations, including diminished phosphorylation of the carboxy-terminal domain of RNA Pol II, and down-regulation of c-MYC, MCL-1, and BCL-xL. Significantly, ectopic expression of these proteins protected cells from THZ1 lethality, documenting the functional significance of reduced expression of these proteins in THZ1 anti-myeloma activity. Notably, CRISPR-Cas knock-out of CDK7 dramatically reduced multiple myeloma cell proliferation, analogous to results observed with CDK7 inhibitors (
Figure 2
).
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Notably, THZ1 interacted synergistically with several agents approved in myeloma (e.g., the proteasome inhibitors bortezomib and carfilzomib), as well as the BH3-mimetic venetoclax which is currently being evaluated in this disease (
Figure 3
). Importantly, THZ1 reduced the survival of primary myeloma cells and their primitive progenitors (CD138-, CD19+, CD20+, CD27+) but was non-toxic to normal CD34+ cells. Finally, THZ1 significantly increased the survival of animals inoculated with U266 multiple myeloma cells in a xenograft model (P = 0.0069;
Figure 4
) without inducing weight loss or other toxicity. Of note, tumors extracted from mice treated with THZ1 displayed down-regulation of c-Myc, MCL-1, and BCL-xL.
Taken together, these findings argue that clinically relevant CDK7 inhibitors, either alone or in combination with established anti-myeloma agents e.g., proteasome inhibitors, warrant attention as a possible therapeutic strategy in multiple myeloma. Efforts to translate these findings into the clinic are currently underway.
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This work was supported by CA205607, CA167708, UH2TR001373, and Leukemia and Lymphoma Society of America Award #R6508-18.
Publication:
About the Investigators: Steven Grant, MD, is Professor of Hematology-Oncology, Internal Medicine, VCU School of Medicine, Associate Director for Translational Research
Program and Shirley Carter and Sture Gordon Olsson Chair in Cancer Research, and Full Member of the VCU Institute of Molecular Medicine (VIMM).
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