Targeting Polo-like kinase in cancer therapy.
Polo-like kinases (Plk) function in mitosis and maintaining DNA integrity. There are four family members, of which Plk1 represents a target for anticancer therapy. Plk1 is only expressed in dividing cells with peak expression during G2/M. Plk1 functions in multiple steps of mitosis, and is overexpressed in many tumor types. Mitotic arrest and inhibition of proliferation, apoptosis, and tumor growth inhibition have been observed in preclinical studies using small interfering RNAs (siRNA) or small molecules that inhibit Plk1. Preclinical studies also show that Plk1 inhibitors may be active against tumors with RAS mutations and that tumor cells with mutations in TP53 are more sensitive to inhibition of Plk1. Several Plk inhibitors are in phase I or II clinical studies. As expected, hematologic toxicity is the primary dose-limiting toxicity. Some patients have achieved clinical response, although in some studies only at doses above the maximum tolerated dose defined in the study. Further evaluation is necessary to discern the clinical utility of Plk1 inhibitors.
Degenhardt
Yan
Y
Cancer Metabolism Drug Discovery Unit, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
Lampkin
Thomas
T
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D002986:Clinical Trials as Topic; D016503:Drug Delivery Systems / Q000379:methods; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D013379:Substrate Specificity; D000097869:Polo-Like Kinase 1
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1