{"doi":"10.1101/2025.11.19.689351","title":"Dual RNA Polymerase I Inhibition with CX-5461 and BMH-21 Synergizes in Breast Cancer by Activating p53-Dependent Stress","abstract":"Hyperactivated ribosomal RNA (rRNA) transcription by RNA polymerase I (Pol I) is a hallmark of cancer and drives elevated ribosome biogenesis required for rapid tumor growth. Several Pol I inhibitors have been identified that induce potent anti-cancer effects. However, clinical application of the first-in-class Pol I inhibitor, CX-5461, has been limited by patient toxicity, which is comparable to other chemotherapies. Identifying synergistic drug combinations offers a promising strategy to maintain on-target anti-cancer effects while minimizing adverse reactions. Synergistic drug combinations involve drugs that enhance each other's effect, enabling dose reduction while preserving efficacy. Synergistic drug combinations of Pol I inhibitors and other anti-cancer agents have been reported; however, it remains unclear whether Pol I inhibitors can synergize with each other. We therefore explored whether two Pol I inhibitors synergize in cancer treatment. We found that CX-5461 and BMH-21 significantly reduced MCF-7 breast cancer cell viability at clinically relevant doses. Combined treatment with these inhibitors led to profound viability defects at sub-micromolar concentrations. Our biochemical analysis showed that CX-5461 and BMH-21 combination therapy enhanced Pol I inhibition and p53 activation compared to monotherapy, promoting growth arrest and apoptosis. Collectively, our findings demonstrate that CX-5461 and BMH-21 are complementary in inhibiting Pol I, activating p53, and suppressing cancer cell growth. Based on these pre-clinical findings, dual Pol I inhibition with CX-5461 and BMH-21 represents a promising therapeutic strategy for treating cancer that is potentially both broadly applicable and tolerable.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":581948,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9505,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1493823,"name":"Kristen Nguyen","orcid":null,"position":1,"is_corresponding":false},{"id":410103,"name":"Bruce A. Knutson","orcid":"0000-0003-3599-1302","position":2,"is_corresponding":false},{"id":879400,"name":"JH Chung","orcid":"0009-0009-2373-3307","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:58:51.328454Z","pmid":"41332727","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}