Novel RNA polymerase I and cyclin-dependent kinase combination therapy for the treatment of aggressive acute myeloid leukemia

Abstract Despite advances in therapy, specific subtypes of Acute Myeloid Leukemia (AML) remain largely incurable. The small molecule drug CX-5461 exhibits dual target specificity, acting as a first-in-class ribosome biogenesis inhibitor to induce the nucleolar surveillance pathway (NSP), as well as to poison Topoisomerase IIα (TOPIIA) to induce DNA damage. We conducted a phenotypic screen of FDA-approved drugs to identify compounds that synergies with CX-5461 to enhance the therapeutic efficacy of this drug in incurable AML. The pan-CDK inhibitors Dinaciclib and Flavopiridol were identified as efficient combinatorial therapies with CX-5461. Dinaciclib acts synergistically across a genetically divergent panel of human AML cell lines, significantly improves survival in murine AML models, and reduces colony formation in primary human AML samples. Synergy was attributable, at least partially, to combinatorial activation of the NSP. Both agents independently stabilized p53 but produced distinct biological outcome; Dinaciclib driving rapid apoptosis and CX-5461 primarily promoting cell-cycle arrest; which together yielded efficient tumor clearance and delayed onset of therapy resistance. These findings provide strong evidence that a combination treatment strategy that leverages nucleolar stress and cell cycle control to enhance treatment outcomes in AML, paving the way for clinical translation of Pol I-CDK co-targeting therapies.