Abstract PO-034: CPSF3 inhibition halts pancreatic cancer cell proliferation by limiting core histone supplies

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with few effective treatment options. Therefore, the need for new therapeutic interventions is urgent. Recently, we have revealed that the gene regulatory process alternative polyadenylation (APA) is highly dysregulated in PDAC patients. APA is a co-transcriptional process that generates distinct transcript isoforms with different 3’ untranslated region (UTR) length, which regulates mRNA stability and gene and protein expression. We found that APA promotes dysregulation of PDAC-promoting genes, predicts poor prognosis in PDAC patients and identified a novel APA-regulated drug target (Venkat et al., Genome Research, 2020). These findings raise the question of whether targeting APA could be a viable therapeutic strategy for PDAC treatment. APA is controlled by a large protein complex assembled on the pre-mRNA, including the cleavage and polyadenylation specificity factor 3 (CPSF3). CPSF3 is an endonuclease that cleaves the pre-mRNA before addition of the polyA tail. Notably, CPSF3 is also a subunit of the histone pre-mRNA processing complex and is critical for the cleavage and processing of core histones. Recently, it was determined that JTE-607, a drug with a long history of safety in humans but no known mechanism of action, is a CPSF3 inhibitor. Subsequently, CPSF3 has been shown to be required for growth of acute myeloid leukemia and Ewing sarcoma cells. However, whether CPSF3 is a potential target in adenocarcinoma is yet to be explored. In PDAC patients, CPSF3 is highly expressed and is associated with unfavorable prognosis. Knockdown or inhibition of CPSF3 decreases PDAC cell proliferation and clonogenicity while having no effect on the growth of non-transformed pancreatic cell lines. Cell cycle analysis and BrdU incorporation assays determined that CPSF3 inhibition arrests cells in early S-phase of the cell cycle. As maintenance of high histone levels are important for the packaging of newly synthesized DNA and progression through the cell cycle, we hypothesized that CPSF3 inhibition decreases PDAC cell proliferation by reducing histone levels. Indeed, CPSF3 inhibition decreased core histone protein levels in a time- and dose-dependent manner. High throughput screening revealed a synergistic effect between JTE-607 and Abexinostat, an HDAC inhibitor, suggesting a novel therapeutic strategy. Therefore, we identify CPSF3 as a druggable target in PDAC and reveal a novel mechanism by which CPSF3 disruption attenuates cell proliferation. Citation Format: Abdulrahman A. Alahmari, Carla Schwarz, Emily Paterson, Swati Venkat, Arwen Tisdale, Michael E. Feigin. CPSF3 inhibition halts pancreatic cancer cell proliferation by limiting core histone supplies [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-034.