Unlocking the therapeutic potential of selective CDK7 and BRD4 Inhibition against multiple myeloma cell growth
Yao Yao,
Shuhui Deng,
Jessica Fong Ng,
Mei Yuan,
Chandraditya Chakraborty,
Vera JoyWeiler,
Nikhil Munshi,
Mariateresa Fulciniti
Affiliations
Yao Yao
Jerome Lipper Multiple Myeloma Disease Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Blood Disease Institute, Key Laboratory of Bone Marrow Stem Cell, Xuzhou Medical University, Xuzhou, China; The Affiliated Hospital of Xuzhou Medical University, Xuzhou
Shuhui Deng
Jerome Lipper Multiple Myeloma Disease Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020
Jessica Fong Ng
Jerome Lipper Multiple Myeloma Disease Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
Mei Yuan
Blood Disease Institute, Key Laboratory of Bone Marrow Stem Cell, Xuzhou Medical University, Xuzhou
Chandraditya Chakraborty
Jerome Lipper Multiple Myeloma Disease Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
Vera JoyWeiler
Jerome Lipper Multiple Myeloma Disease Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
Nikhil Munshi
Jerome Lipper Multiple Myeloma Disease Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; VA Boston Healthcare System, Boston, MA
Mariateresa Fulciniti
Jerome Lipper Multiple Myeloma Disease Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
Multiple myeloma (MM) is a plasma cell malignancy 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 single-agent therapy in both cell lines and patient cells. This synergistic activity was also observed in Waldenström’s 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 combination therapy’s potential as a therapeutic strategy in MM and WM.
