Targeting cyclins and cyclin-dependent kinases in cancer: lessons from mice, hopes for therapeutic applications in human.
The activity of cyclins and their associated cyclin-dependent kinases (CDKs) is frequently deranged in human cancers. For this reason, cyclin-CDK complexes have been considered as very promising therapeutic targets in human malignancies. An obvious concern, however, is whether blocking cyclin-CDK function would preferentially affect cancer cells, but not normal, non-transformed cells. Two recent reports addressed the requirement for cyclin D1-CDK4 kinase in mouse development versus in neoplasia. These studies documented that the kinase activity of cyclin D1-CDK complexes is largely dispensable for normal development, but it is critically required for the initiation and maintenance of mammary carcinomas. Here we summarize the lessons learned from mouse knockout experiments, and discuss the utility of CDK inhibitors in therapy of human cancers, and possibly of other diseases.
Lee
Young-mi
YM
Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Sicinski
Piotr
P
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics / Q000378:metabolism; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics
D016213:Cyclins; D004791:Enzyme Inhibitors; D018844:Cyclin-Dependent Kinases