Abstract B035: Targeting ribosome biogenesis addition is a novel strategy for pancreatic cancer therapy

Abstract

Abstract Pancreatic cancer (PanCa) is the third leading cause of cancer-related deaths in the United States with limited therapeutic options available. Gemcitabine (GEM), a deoxycytidine nucleoside analog is currently considered the most effective therapy for PanCa; however, it shows only a marginal survival benefit of 6 months. PanCa cells are addicted to ribosome biogenesis (RiBi) which supports their high rate of growth and proliferation. Therefore, strategically targeting the process of RiBi could be one of the ideal strategies for the prevention and treatment of PanCa. In this study, we for the first-time report that RPA194, a catalytic subunit of RNA Pol I is differentially expressed in normal pancreatic ductal epithelial (NPDE) and cancer cells. We also observed differential expression of RPA194 in various grades of pancreatic tumor tissues and its level was increased in high-grade pancreatic tumor tissues. We tested our hypothesis that targeting RPA194 with a non-toxic pharmacological inhibitor (BMH-21) will inhibit the growth of advanced PanCa. We observed that BMH-21 inhibits the growth and induced apoptosis of PanCa cells in a dose-dependent manner and this inhibition was correlated with the expression of RPA194. We observed proteasomal mediated degradation of RPA194 in PanCa cells. BMH-21 treatment inhibited RPA194 occupancy on rDNA but did not affect other nucleolar proteins (UBF, fibrillarin, nucleolin, and nucleophosmin). Two times the effective concentration of BMH-21 (5 µM) did not show any cytotoxic effect in NPDE cells. However, BMH-21 degraded RPA 194 protein in these cells in a similar manner as in PanCa cells. Therefore, we speculate that other proteins are involved in the selective toxicity of BMH-21 in PanCa cells. These findings were translated to in vivo model systems. We observed that BMH-21 significantly (P<0.01) inhibited the growth of pancreatic tumors in an orthotopic xenograft model. This pancreatic tumor growth inhibition was correlated with degradation of RPA194 protein in BMH-21 treated mice tumor tissues followed by inhibition of cell proliferation markers (ki67 and PCNA). Taken together, our results strongly suggest that targeting the RiBi process is a novel approach and BMH-21 is a non-toxic potential targeting agent for the prevention and treatment of advanced PaCa. Citation Format: Mudassier Ahmad, Carlos Perez, Andrew Massey, Vivek Kashyap, Neeraj Chauhan, Haider Ahsan, Jasmine Jasmine, Manish Tripathi, Subhash Chauhan, Bilal Hafeez. Targeting ribosome biogenesis addition is a novel strategy for pancreatic cancer therapy [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B035.