Abstract 271: BMH-21, an RNA polymerase I inhibitor provides a novel mechanism to target Δp53 and R248Wp53 driven pancreatic cancers

Abstract p53 mutations occur in 50-75 % of pancreatic cancer cases. p53 mutations promote the protein turnover and increase the dependence of cancer cells on ribosome biogenesis as compared to normal cells. We report that BMH-21, which is an RNA Polymerase I inhibitor can be used to inhibit the growth of Δp53 (truncated p53) and R248Wp53 driven pancreatic cancers. Our studies show that BMH-21 induced degradation of RPA194 (a catalytic subunit of RNA Polymerase I) has a very less cytotoxic effect on normal human pancreatic ductal epithelial cells. The p53 mutations in PanCa cells were found to play an important role in the recruitment of catalytic subunits of RNA polymerase I (RPA194 and RPA135) on ribosomal DNA (rDNA). BMH-21 decreases the recruitment of RPA194 on rDNA in Capan-2 cells that express p53 wild type and recruitment of both RPA194 and RPA135 on rDNA in MIA PaCa-2 cells that express R248W p53. We found that p53 wild type (WT) and mutant p53 physically interact with both the catalytic subunits of RNA polymerase I. BMH-21 induced degradation of RPA194 was found to expose Δp53 and R248Wp53 for ubiquitination. No ubiquitination of p53 WT was observed in BMH-21 treated Capan-2 cells. RNA polymerase inhibitors induce nucleolar stress that promotes p53 expression. BMH-21 induced ubiquitination of p53 prevents increases in expression of Δp53 and R248Wp53p53 which restricts the role of mutant p53s in the proliferation of PanCa cells. BMH-21 treatment reduces the growth of orthotopic xenograft pancreatic tumors in athymic nude mice with no observed toxicity. These findings suggest that BMH-21 is a promising therapeutic agent for treatment of PanCa. Citation Format: Mudassier Ahmad, Sahir Sultan Alvi, Haider Ahsan, Carlos Perez, Andrew Massey, Vivek Kashyap, Neeraj Chauhan, Emmanuel Anning, Manish Tripathi, Dae Joon Kim, Nirakar Sahoo, Tamer Oraby, Mohammad Moshahid Khan, Manu Sebastian, Subhash C. Chauhan, Bilal Bin Hafeez. BMH-21, an RNA polymerase I inhibitor provides a novel mechanism to target Δp53 and R248Wp53 driven pancreatic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 271.