Targeting the Protein Regulator of Cytokinesis 1 (PRC1) Pathway in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer-related mortality worldwide, largely due to its high recurrence rate and resistance to chemotherapy. Our study identifies the microtubule-associated protein regulator of cytokinesis 1 (PRC1) as a key driver of PDAC progression, correlating with poor prognosis, increased cancer proliferation, stemness, metastasis, and chemoresistance. Elevated PRC1 expression appears to contribute significantly to PDAC pathogenesis.

Using siRNA and the small-molecule inhibitor BKT300, we demonstrated that PRC1 downregulation induces G2/M cell cycle arrest, leading to mitotic catastrophe and apoptosis via the caspase-3 pathway. Notably, BKT300 selectively targets PRC1 by trapping it in a phosphorylated state at T481 while simultaneously downregulating CDC25C and upregulating p21. siRNA-mediated PRC1 suppression abrogated BKT300’s activity, indicating that its therapeutic efficacy is PRC1-dependent. Direct binding of BKT300 to PRC1 was further validated through multiple biochemical assays.

Crucially, BKT300 synergized with 5-fluorouracil (5-FU) and irinotecan—both standard-of-care chemotherapeutics for PDAC—to enhance cancer cell death. In vivo studies in PDAC mouse models demonstrated significant tumor growth inhibition and regression, highlighting BKT300’s therapeutic potential.

Overall, BKT300 represents a novel, PRC1-targeted approach for PDAC treatment, offering a promising strategy to improve outcomes in patients with high PRC1 expression and resistance to conventional therapies.