Targeting CDK9 inhibits the growth of KMT2A-rearranged infant leukemia and demonstrates synergy with menin inhibition.
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The KMT2A-rearranged (KMT2A-r) leukemia is one of the most challenging cancers to treat in children, owing to the higher relapse rates and chemoresistance frequently observed in this patient population. At the molecular level, chromosomal translocation in the KMT2A gene leads to a deregulated epigenetic landscape resulting in the upregulation of transcription factors like HOXA9, consequently contributing to leukemogenesis. One crucial component of the oncogenic KMT2A-r complex is the involvement of positive transcription elongation factor b, which is composed of cyclin T and cyclin-dependent kinase 9 (CDK9), which leads to the dysregulation of transcriptional elongation. This study investigated the function of enitociclib, a small molecule CDK9 inhibitor in clinical development that has shown effective activity in other tumor types. Enitociclib showed growth inhibition and an on-target effect in KMT2A-r leukemic cells with a significant decrease in MYC and MCL-1 protein levels. Moreover, enitociclib was found to reduce the growth advantage provided to leukemic cells by the bone marrow microenvironment. In addition, it demonstrates the ability to synergize with menin inhibitors, leading to an effective decrease in HOXA9 protein levels in KMT2A-r infant leukemia cells. Enitociclib also potentiates the cytotoxicity of venetoclax in relatively venetoclax-resistant KMT2A-r leukemic cells. Overall, enitociclib has shown measurable in vitro antitumor activity in KMT2A-r infant leukemia and is a rational therapeutic option to explore in future clinical trials.