A PLK4 Inhibitor Has Single-Agent Activity in Preclinical Tumor Models

Polo-like kinase 4 (PLK4) is a mitotic kinase that regulates centriole duplication. PLK4 depletion arrests centriole duplication and has been shown to have a synthetic lethal interaction with PTEN deficiency, suggesting PLK4 may be a therapeutic target. In an siRNA screen of kinase and kinase-related genes in a panel of breast cancer cell lines, Mason and colleagues found that 50% of cell lines were dependent on PLK4 for survival, especially triple-negative breast cancer (TNBC) and immortalized basal breast cell lines. Consistent with these findings suggesting that PLK4 may contribute to breast cancer survival, analysis of breast cancer gene expression data sets revealed that PLK4 was overexpressed in 26% of tumors overall and 48% of TNBCs, and knockdown of PLK4 inhibited growth of breast cancer cells in vivo. Prompted by these studies, the authors developed a small-molecule inhibitor of PLK4, CFI-400945, that potently and selectively inhibits PLK4 in vitro, but also has activity against AURKB, TRKA, TRKB, and TEK. CFI-400945 treatment led to aberrant centriole duplication and abnormal mitoses in vitro that ultimately caused cell death or cell-cycle arrest. Endoreplication and cytokinesis defects were also observed, suggesting that some effects of CFI-400945 may also be due to its activity against AURKB. Oral administration of CFI-400945 was well tolerated in multiple xenograft models and mouse strains, and had favorable pharmacokinetics. CFI-400945 also had single-agent antitumor activity in vivo, specifically against PTEN-deficient xenografts, and induced significant regression of a patient-derived xenograft model of PTEN-null TNBC in association with induction of aberrant mitoses. Although further work is needed to understand the mechanistic basis for increased sensitivity of PTEN-null tumors to PLK4 inhibition, these findings support clinical testing of CFI-400945 in a phase I trial, which has been initiated, and suggest that PTEN deficiency may be a predictive biomarker of CFI-400945 response.

Mason JM, Lin DC, Wei X, Che Y, Yao Y, Kiarash R, et al. Functional characterization of CFI-400945, a polo-like kinase 4 inhibitor, as a potential anticancer agent. Cancer Cell 2014 Jul 17 [Epub ahead of print].