Cyclin-dependent kinase inhibitors and the treatment of gastrointestinal cancers.
The cell cycle is a highly conserved and tightly regulated biological system that controls cellular proliferation and differentiation. The cell cycle regulatory proteins, which include the cyclins, the cyclin-dependent kinases (CDKs), and the CDK inhibitors, are critical for the proper temporal and spatial regulation of cellular proliferation. Conversely, alterations in cell cycle regulatory proteins, leading to the loss of normal cell-cycle control, are a hallmark of many cancers, including gastrointestinal cancers. Accordingly, overexpression of CDKs and cyclins and by contrast loss of CDK inhibitors, are all linked to gastrointestinal cancers and are often associated with less favorable prognoses and outcomes. Because of the importance that the cell cycle regulatory proteins play in tumorigenesis, currently there is a broad spectrum of cell-cycle inhibitors under development that, as a group, hold promise as effective cancer treatments. In support of this approach to cancer treatment, the growing availability of molecular diagnostics techniques may help in identifying patients who have driving abnormalities in the cell-cycle machinery and are thus more likely to respond to cell-cycle inhibitors. In this review, we discuss the prevalence of cell-cycle abnormalities in patients with gastrointestinal cancers and provide a preclinical and clinical overview of new agents that target cell-cycle abnormalities with a special emphasis on gastrointestinal cancers.
James Cancer Hospital and Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
Sameh
S
Mikhail
Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia; Department of Pathology, Georgetown University Medical Center, Washington, District of Columbia. Electronic address: albanese@georgetown.edu.
Christopher
C
Albanese
Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia.
Michael J
MJ
Pishvaian
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000201:enzymology
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D018844:Cyclin-Dependent Kinases