Abstract 3950: Targeting ribosome biogenesis is a novel strategy to suppress the growth of pancreatic cancer

Abstract

Abstract Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States with limited therapeutic approaches. Dysregulation of the ribosome biogenesis process was observed in various cancer including pancreatic cancer. Therefore, strategically targeting ribosome biogenesis could be a novel approach for pancreatic cancer treatment. One such approach is to target ribosome biogenesis is via small molecule inhibitors of RNA Polymerase I as these inhibitors have shown promising anti-cancer activity in pre-clinical and clinical studies. We observed differential constitutive expression of various ribosomal proteins including RPA-194 in human PanCa cells when compared with normal HPDE cells. Therefore, we hypothesized that targeting RNA pol I will inhibit the growth of pancreatic cancer. In this study, we for the first time evaluated the therapeutic effect of a novel RNA polymerase I inhibitor (BMH-21) against PanCa in pre-clinical model systems. BMH-21 significantly inhibited the ribosome biogenesis process in various pancreatic cancer cells (Panc-1, AsPC1, BxPC3, MiaPaCa-2) as determined by inhibition of rRNA synthesis and POL I occupancy on rDNA. BMH-21 treatment of pancreatic cancer cells significantly degraded RPA194 protein as determined by Western blot and confocal microscopy analysis. BMH-21 treatment (0.25-5µM) showed differential IC50 in various pancreatic cancer cells which were correlated with the expression of its target proteins RPA194 and RPA135 expression. In our flow cytometry experiment, we observed a significant G0/G1 cell cycle arrest and increase Annexin V and Annexin V7-AAD positive cells in BMH-21 treated pancreatic cancer cells as compared to the vehicle treatment group suggesting its apoptosis-inducing potential in pancreatic cancer cells. BMH-21 treatment inhibited growth and metastatic phenotypes of various PanCa cells as analyzed by various functional assays (colony formation and atomic force microscopy analyses). We also evaluated the effect of BMH-21 on various kinases, which regulate ribosome biogenesis. Interestingly, we observed BMH-21 significantly (P<0.01) downregulated the phosphorylation of AKT (Ser473) and WNK-1 (Thr60) kinases and Stat3 phosphorylation at Ser727 and upregulates pChk2 kinase in PanCa cells. BMH-21 (2 mg/kg i.p) significantly (P<0.01) inhibited the growth of pancreatic tumor in an orthotopic xenograft mouse model. Excised tumor tissues of BMH-21 treated mice showed decreased expression of various ribosomal proteins including RPA194 and RPA195 along with various cell proliferative markers (ki67 and PCNA) as compared to vehicle-treated group. Taken together, our results demonstrated that targeting the ribosome biogenesis process is a novel therapeutic strategy for the management of pancreatic cancer and BMH-21 could be used as a potential therapeutic agent for the treatment of advanced pancreatic cancer. Citation Format: Carlos Perez, Mudassier Ahmad, Andrew Massey, Asif Shahriar, Emmanuel Anning, Vivek Kashyap, Neeraj Chauhan, Anupam Dhasmana, Manish Tripathi, Subhash Chauhan, Bilal Hafeez. Targeting ribosome biogenesis is a novel strategy to suppress the growth of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3950.