Inhibition of CDK1 as a potential therapy for tumors over-expressing MYC.
Tumor cells have a dysregulated cell cycle that may render their proliferation especially sensitive to the inhibition of cyclin-dependent kinases (CDKs), important regulators of cell cycle progression. We examined the effects of CDK1 inhibition in the context of different oncogenic signals. Cells transformed with MYC, but not cells transformed by a panel of other activated oncogenes, rapidly underwent apoptosis when treated with small-molecule CDK1 inhibitors. The inhibitor of apoptosis protein BIRC5 (survivin), a known CDK1 target, is required for the survival of cells overexpressing MYC. Inhibition of CDK1 rapidly downregulates survivin expression and induces MYC-dependent apoptosis. CDK1 inhibitor treatment of MYC-dependent mouse lymphoma and hepatoblastoma tumors decreased tumor growth and prolonged their survival. As there are no effective small-molecule inhibitors that selectively target the MYC pathway, we propose that CDK1 inhibition might therefore be useful in the treatment of human malignancies that overexpress MYC.
Goga
Andrei
A
Department of Medicine, Division of Hematology/Oncology, University of California, San Francisco, San Francisco, California 94143-0552, USA. andrei.goga@ucsf.edu
Yang
Dun
D
Tward
Aaron D
AD
Morgan
David O
DO
Bishop
J Michael
JM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008223:Lymphoma / Q000188:drug therapy / Q000235:genetics; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism*; D051381:Rats; D000077022:Survivin; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D004791:Enzyme Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D016271:Proto-Oncogene Proteins c-myc; D000077022:Survivin; D016159:Tumor Suppressor Protein p53; D016203:CDC2 Protein Kinase