Polo-Like Kinases in Colorectal Cancer: Potential for Targeted Therapy

Abstract

The five individual members of the mammalian polo-like kinase family play non-redundant roles in centriole replication and maturation, mitotic progression, cytokinesis, and the DNA damage response. In human colorectal cancer, Plk1 and Plk4 are expressed at higher levels in tumor than adjacent normal mucosa, and the degree of overexpression correlates with adverse prognosis. In colorectal cancer cell lines, suppression of Plk1 activity leads to mitotic arrest and apoptosis, while inhibition of Plk4 activity reduces tumor growth and invasion. Inhibition of Plk1 or Plk4 in mice using orally bioavailable agents reduces the growth of human colorectal cancer xenografts. On the basis of these preclinical studies, clinical trials of several different targeted anti-Plk1 agents have been undertaken in patients with advanced solid tumors, and a phase I trial of the anti-Plk4 inhibitor CFI-400945 is currently accruing. Here, we review the rationale, results, and potential limitations of Plks as therapeutic targets. Evidence from genetic mouse models suggests that Plk1, Plk2, Plk3, and Plk4 may all possess tumor suppressive activity, particularly with aging. Thus, enthusiasm for the use of targeted Plk inhibitors in cancer therapy must be tempered somewhat by the potential for development of second primary tumors in the long term.