Targeting CDK7 to overcome hypomethylating agent resistance in acute myeloid leukemia

PURPOSE: Hypomethylating agents (HMAs), such as azacitidine and decitabine, are widely used in elderly or medically unfit patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). However, most patients eventually develop primary or acquired resistance and outcomes following HMA failure remain poor, particularly in transplantation-ineligible patients. This study evaluated the efficacy of CDK7 inhibition as a therapeutic strategy for overcoming HMA resistance in vitro. METHODS: HMA-resistant AML cells (MOLM/AZA-1 and MOLM/DEC-5) were generated to evaluate the therapeutic activity of the CDK7 inhibitor, YPN-005. Cell viability was assessed using a CellTiter-Glo assay. Western blotting was performed to examine the dysregulation of DNA methyltransferases (DNMTs) and apoptotic markers. Cell cycle distribution and apoptosis were evaluated using flow cytometry. Transcriptomic changes were analyzed using quantitative reverse transcription polymerase chain reaction. RESULTS: YPN-005 demonstrated potent growth-inhibitory effects in HMA-resistant AML cells, with an efficacy comparable to that observed in parental MOLM-13 cells. Mechanistically, CDK7 inhibition reduced DNMT expression and decreased the phosphorylation of RNA polymerase II (Ser2/5/7). YPN-005 significantly induced apoptosis, as evidenced by increased Annexin V positivity and the activation of PARP and caspase-3. Notably, CD40 expression was markedly upregulated at both the transcript and protein levels. CONCLUSION: CDK7 inhibition effectively induces apoptosis in HMA-resistant AML cells by suppressing RNA polymerase II phosphorylation and downregulating aberrant DNMT expression. Furthermore, the induction of CD40 suggests a potential role for CDK7 blockade in modulating immunophenotypic features. These findings support CDK7 inhibition as a promising therapeutic strategy for overcoming resistance to epigenetic therapies in patients with AML/MDS.