Targeting CDK7 to overcome hypomethylating agent resistance in acute myeloid leukemia

Abstract

Abstract 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 to overcome HMA resistance in vitro . Methods HMA-resistant AML cell lines (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 CellTiter-Glo assays. Western blot analysis was performed to examine dysregulation of DNA methyltransferases (DNMTs) and apoptotic markers. Cell cycle distribution and apoptosis were evaluated by flow cytometry. Transcriptomic changes were analyzed using quantitative reverse transcription polymerase chain reaction arrays. Results YPN-005 demonstrated potent growth-inhibitory effects in HMA-resistant cells, with efficacy comparable to that observed in parental MOLM-13 cells. Mechanistically, CDK7 inhibition reduced DNMT expression and decreased RNA polymerase II (Ser2/5/7) phosphorylation. YPN-005 significantly induced apoptosis, as evidenced by increased Annexin V positivity and activation of PARP and caspase-3. Notably, CD40 expression was markedly upregulated at 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, induction of CD40 suggests a potential role for CDK7 blockade in modulating immunophenotypic features. These findings support CDK7 inhibition as a promising therapeutic strategy to overcome resistance to epigenetic therapies in AML/MDS.