Polo-like kinase 1 (Plk1) plays an important role in cell cycle regulation. Recent work has suggested that Plk1 could be a biomarker of gemcitabine response in pancreatic ductal adenocarcinoma (PDAC). Although targeting Plk1 to treat PDAC has been attempted in clinical trials, the results were not promising, and the mechanisms of resistance to Plk1 inhibition is poorly understood. In addition, the role of Plk1 in PDAC progression requires further elucidation. Here, we showed that Plk1 was associated with poor outcomes in PDAC patients. In an inducible transgenic mouse line with specific expression of Plk1 in the pancreas, Plk1 overexpression significantly inhibited caerulein-induced acute pancreatitis and delayed development of acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN). Bioinformatics analyses identified the regulatory networks in which Plk1 is involved in PDAC disease progression, including multiple inflammation-related pathways. Unexpectedly, inhibition or depletion of Plk1 resulted in upregulation of PD-L1 via activation of the NFκB pathway. Mechanistically, Plk1-mediated phosphorylation of RB at S758 inhibited the translocation of NFκB to nucleus, inactivating the pathway. Inhibition of Plk1 sensitized PDAC to immune checkpoint blockade therapy through activation of an anti-tumor immune response. Together, Plk1 suppresses PDAC progression and inhibits NFκB activity, and targeting Plk1 can potentiate the efficacy of immunotherapy in PDAC.

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