CDK7 controls E2F- and MYC-driven proliferative and metabolic vulnerabilities in multiple myeloma.

Autor:	Yao Y; Jerome Lipper Multiple Myeloma Disease Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.; Blood Disease Institute, Key Laboratory of Bone Marrow Stem Cell, Xuzhou Medical University, Xuzhou, China., Ng JF; Jerome Lipper Multiple Myeloma Disease Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA., Park WD; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX., Samur M; Jerome Lipper Multiple Myeloma Disease Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA., Morelli E; Jerome Lipper Multiple Myeloma Disease Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA., Encinas Mayoral J; University Hospital October 12, Madrid, Spain., Chyra Z; Jerome Lipper Multiple Myeloma Disease Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA., Xu Y; Jerome Lipper Multiple Myeloma Disease Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA., Derebail S; Jerome Lipper Multiple Myeloma Disease Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA., Epstein C; Broad Institute, Cambridge, MA., Nabet B; Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA., Chesi M; Comprehensive Cancer Center, Mayo Clinic, Scottsdale, AZ., Gray NS; Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford Medical School, Stanford, CA., Young RA; Whitehead Institute for Biomedical Research, Cambridge, MA., Kwiatkowski N; Kymera Therapeutics, Watertown, MA., Mitsiades C; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA., Anderson KC; Jerome Lipper Multiple Myeloma Disease Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA., Lin CY; Kronos Bio, Cambridge, MA., Munshi NC; Jerome Lipper Multiple Myeloma Disease Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.; VA Boston Healthcare System, Boston, MA., Fulciniti M; Jerome Lipper Multiple Myeloma Disease Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2023 Jun 08; Vol. 141 (23), pp. 2841-2852.
DOI:	10.1182/blood.2022018885
Abstrakt:	Therapeutic targeting of CDK7 has proven beneficial in preclinical studies, yet the off-target effects of currently available CDK7 inhibitors make it difficult to pinpoint the exact mechanisms behind MM cell death mediated by CDK7 inhibition. Here, we show that CDK7 expression positively correlates with E2F and MYC transcriptional programs in cells from patients with multiple myeloma (MM); its selective targeting counteracts E2F activity via perturbation of the cyclin-dependent kinases/Rb axis and impairs MYC-regulated metabolic gene signatures translating into defects in glycolysis and reduced levels of lactate production in MM cells. CDK7 inhibition using the covalent small-molecule inhibitor YKL-5-124 elicits a strong therapeutic response with minimal effects on normal cells, and causes in vivo tumor regression, increasing survival in several mouse models of MM including a genetically engineered mouse model of MYC-dependent MM. Through its role as a critical cofactor and regulator of MYC and E2F activity, CDK7 is therefore a master regulator of oncogenic cellular programs supporting MM growth and survival, and a valuable therapeutic target providing rationale for development of YKL-5-124 for clinical use. (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution.)
Databáze:	MEDLINE
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