Abstract A056: Targeting the Protein Regulator of Cytokinesis 1 (PRC1) Pathway in Pancreatic Cancer

Pancreatic cancer (PDAC) is a major cause of cancer mortality worldwide, largely due to its high recurrence rate and chemoresistance. We found that the microtubule-associated protein regulator of cytokinesis 1 (PRC1) is implicated in PDAC progression, associated with poor prognosis, enhanced cancer proliferation, stemness, metastasis, and chemoresistance. PRC1 functions as an oncogenic driver, particularly in PDAC cases with elevated expression. Using siRNA and the small molecule BKT300 that inhibits PRC1 function, we found that downmodulation of PRC1 induces G2/M cell cycle arrest and triggered mitotic catastrophe and apoptosis. Interestingly, BKT300 targeted PRC1 by arresting it in a phosphorylated state at T481, concurrently downregulating CDC25C and upregulating p21. siRNA-mediated suppression of PRC1 in cancer cells prevented the activity of BKT300, indicating that BKT300’s efficacy is dependent on PRC1 expression. Direct binding of BKT300 to PRC1 was further confirmed through multiple assays. Importantly, BKT300 synergized with 5FU and irinotecan to induce cancer cell death, both agents are the standard of care for treatment of pancreatic cancer patients. In vivo studies in PDAC mouse models demonstrated significant tumor growth inhibition and tumor regression, underscoring the therapeutic promise of BKT300 for PDAC. Overall, BKT300 presents a novel approach to tackling PDAC by directly targeting PRC1, potentially improving outcomes in PDAC cases with high PRC1 expression and resistance to conventional therapies. Citation Format: Amnon Peled, Michal Abraham, Lika Gamaev, Orly Eizenberg, Arnon Aharon. Targeting the Protein Regulator of Cytokinesis 1 (PRC1) Pathway in Pancreatic Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3): nr A056.