All screens lead to polo-like kinase 1: A central node in cancer therapeutics and resistance.

Polo-like kinase 1 (PLK1) is a mitotic kinase that is frequently overexpressed across many cancer types and strongly associated with poor prognosis and resistance to treatment. Comprehensive genomic, genetic, and pharmacological screens consistently pinpoint PLK1 as a therapeutic target in oncology. Despite promising preclinical anti-tumor efficacy of PLK1 inhibitors, clinical outcome as a monotherapy has been modest, necessitating the development of next-generation PLK1 inhibitors and combination strategies. The role of PLK1 extends beyond cell cycle regulation to tumor progression, immune evasion, and the tumor microenvironment. Emerging evidence supports synergistic potential of new-generation PLK1 inhibitors, such as Onvansertib, with chemo- and immune-therapies. This mini-review and perspective present current insights on PLK1 overexpression and its mechanistic impact on cancer aggressiveness and therapy resistance. We highlight the need for refined patient stratification and innovative combination regimens to exploit PLK1 inhibition in cancer treatment.