PLK4: Master Regulator of Centriole Duplication and Its Therapeutic Potential

Centrosomes catalyze the assembly of a microtubule-based bipolar spindle, essential for the precise chromosome segregation during cell division. At the center of this process lies Polo-Like Kinase 4 (PLK4), the master regulator that controls the duplication of the centriolar core to ensure the correct balance of two centrosomes per dividing cell. Disruptions in centrosome number or function can lead to genetic disorders such as primary microcephaly or drive tumorigenesis via centrosome amplification. In this context, several chemical inhibitors of PLK4 have emerged as promising therapeutic candidates. The inhibition of PLK4 results in the emergence of acentrosomal cells, which undergo prolonged and error-prone mitosis. This aberrant mitotic duration triggers a "mitotic stopwatch" mechanism that activates the tumor suppressor p53, halting cellular proliferation. However, in a multitude of cancers, the efficacy of this mitotic surveillance mechanism is compromised by mutations that incapacitate p53. Recent investigations have unveiled p53-independent vulnerabilities in cancers characterized by chromosomal gain or amplification of 17q23, which encodes for the ubiquitin ligase TRIM37, in response to PLK4 inhibition, particularly in neuroblastoma and breast cancer. This review encapsulates the latest advancements in our understanding of centriole duplication and acentrosomal cell division in the context of TRIM37 amplification, positioning PLK4 as a compelling target for innovative cancer therapeutics.