Role of Polo-Like Kinase 4 (PLK4) in Epithelial Cancers and Recent Progress in its Small Molecule Targeting for Cancer Management

Abstract

The polo-like kinases (PLKs) are a family of serine/threonine kinases traditionally linked to cell cycle regulation. A structurally unique member of this family, PLK4, has been shown to regulate centriole duplication during the cell cycle via interactions with a variety of centrosomal proteins. Recent findings suggest that PLK4 is overexpressed in various human cancers and associated with poor cancer prognosis. Although several studies have shown that PLK4 inhibition may lead to cancer cell death, the underlying mechanisms are largely unknown. In this review, we discuss the structure, localization and function of PLK4, along with the functional significance of PLK4 in epithelial cancers and some preliminary work suggesting a role for PLK4 in the key cancer progression process epithelial-mesenchymal transition (EMT). We also discuss the potential of PLK4 as a druggable target for anti-cancer drug development based on critical analysis of the available data of PLK4 inhibitors in pre-clinical development and clinical trials. Overall, the emerging data suggests that PLK4 plays an essential role in epithelial cancers and should be further explored as a potential biomarker and/or therapeutic target. Continued detailed exploration of available and next-generation PLK4 inhibitors may provide a new dimension for novel cancer therapeutics following successful clinical trials.

Modelling the Functions of Polo-Like Kinases in Mice and Their Applications as Cancer Targets with a Special Focus on Ovarian Cancer

“…These motifs are known as the polo-box domain which is unique to the PLK family (for reviews see [ 7 , 8 ]). PLK4 is singular and the least representative family member with respect to its triple polo-box architecture including a cryptic dimeric one [ 9 ], for reviews see [ 10 , 11 ]. Catalytic as well as regulatory domains are evolutionary highly conserved.…”

“…The protein is quickly degraded (reviewed by [ 26 ]). PLK4 is essential for centriole biogenesis driving centriole duplication and mitotic progression [ 84 , 85 , 86 , 87 ], for reviews see [ 6 , 10 , 11 , 47 , 88 , 89 ]. Like PLK1, PLK4 acts as an integrative protein involved in the control of cell division.…”

“…As accounts for PLK1 , PLK4 is overexpressed in a variety of solid tumors and hematologic malignancies considered to act as an oncogene (for reviews see [ 11 , 89 ]). High levels of PLK4 correlate with tumor growth, aggressive progression and treatment resistance representing a poor-prognostic marker.…”

“…High levels of PLK4 correlate with tumor growth, aggressive progression and treatment resistance representing a poor-prognostic marker. This accounts for a variety of malignancies including several epithelial cancer types (reviewed by [ 11 , 89 ]) such as breast cancer [ 196 , 197 , 198 , 199 ], lung cancer [ 200 , 201 ], prostate cancer [ 202 ], and gastric cancer [ 203 , 204 ], but also for neuroblastoma [ 205 ], glioblastoma [ 206 ], and acute leukemia [ 207 , 208 ]. In skin epidermis, overexpression of PLK4 leads to hyperplasia [ 209 ] and promotes—in association with p53 deficiency—tumorigenesis causing hyperproliferation and abnormal differentiation of basal keratinocytes and melanocytes [ 209 , 210 ].…”

“…This pathway is supposed having a tumor-promoting function in several cancers. In addition, PLK4 induces epithelial-mesenchymal transition (for reviews see [ 11 , 89 ], which is one of the key processes in aggressive tumorigenesis as depicted for oncogenic function of overexpressed PLK1 (see above). Cancer cell motility and invasiveness imply dynamic cytoskeletal re-organization and junctional cell-cell as well as cell-matrix (re)modelling [ 161 , 162 ].…”