Plk1 Inhibitors in Cancer Therapy: From Laboratory to Clinics

Abstract

Polo-like kinase 1 (Plk1) overexpression has been shown to occur in a wide range of tumors, prompting research and development of Plk1 inhibitors as a means of cancer treatment. This review discusses recent advances in the development of Plk1 inhibitors for cancer management. Plk1 inhibition has been shown to cause mitotic block and apoptosis of cells with higher mitotic index and therefore higher Plk1 expression. The potential of Plk1 inhibitors as cancer therapeutics has been widely investigated. However, a complete understanding of Plk1 biology/mechanism is yet to be fully achieved. Resistance to certain chemotherapeutic drugs has been linked to Plk1 overexpression, and Plk1-mediated mitotic events such as microtubule rearrangement have been found to reduce the efficacy of chemotherapeutic agents. The Plk1 inhibitor volasertib has shown considerable promise in clinical studies, having reached phase III trials. However, preclinical success with Plk1 inhibitors has not translated well into clinical success. In our view, combined therapies targeting other relevant pathways together with Plk1 may be vital to combat issues observed with monotherapy, especially resistance. In addition, research should also be directed toward understanding the mechanisms of Plk1 and designing additional next generations of specific, potent Plk1 inhibitors to target cancer. Mol Cancer Ther; 15(7); 1427-35. ©2016 AACR.

Figure 1. Plk family proteins

The structures of the five Plk family member proteins are shown. The location of the kinase domains (KD) is shown in blue, whereas the polo box domains (PB) are represented in orange.

Figure 2. Examples of how Plk1-associated kinase activity contributes to therapy resistance

(A) Plk1 phosphorylation of its substrates GTSE-1 and Topors causes p53 inactivation which results in doxorubicin resistance (25, 26). (B) Plk1-associated kinase activity drives DNA replication under stress via modulating its substrates Hbo1 and Orc2, resulting in acquired gemcitabine resistance in pancreatic cancer cells (32, 34, 35). (C) Plk1 contributes to paclitaxel resistance by phosphorylating its substrates CLIP-170, p150^Glued and Sgt1, thereby regulating microtubule dynamics and microtubule-kinetochore attachment (41-44). (D) Plk1-associated activation of AR signaling leads to ASI resistance in CRPC (47, 49). (E) Plk1 elevation causes inactivation of PTEN to modulate the metabolism in prostate cancer cells (56). (F) Inhibition of Plk1 enhances the efficacy of anti-neoplastic activity of metformin in prostate cancer via both p53 and metabolic pathways (52).