Interrogation of novel CDK2/9 inhibitor fadraciclib (CYC065) as a potential therapeutic approach for AML

• Published in: Cell death discovery Vol. 7; no. 1; p. 137
• Main Authors: Chantkran, Wittawat, Hsieh, Ya-Ching, Zheleva, Daniella, Frame, Sheelagh, Wheadon, Helen, Copland, Mhairi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10-06-2021; Springer Nature B.V; Nature Publishing Group
• Subjects: 631/67/1990/283/1897; 692/308/2778; Acute myeloid leukemia; Apoptosis; Bcl-2 protein; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Cycle Analysis; Chemotherapy; Cyclin-dependent kinase 2; Cyclin-dependent kinases; Cytarabine; Cytogenetics; DNA-directed RNA polymerase; Enzyme inhibitors; Genetic diversity; Intolerance; Kinases; Leukemia; Life Sciences; Mcl-1 protein; Myeloid leukemia; RNA polymerase; Stem Cells; Transcription; Tumor cell lines
• ISSN: 2058-7716; 2058-7716
• DOI: 10.1038/s41420-021-00496-y

Over the last 50 years, there has been a steady improvement in the treatment outcome of acute myeloid leukemia (AML). However, median survival in the elderly is still poor due to intolerance to intensive chemotherapy and higher numbers of patients with adverse cytogenetics. Fadraciclib (CYC065), a novel cyclin-dependent kinase (CDK) 2/9 inhibitor, has preclinical efficacy in AML. In AML cell lines, myeloid cell leukemia 1 (MCL-1) was downregulated following treatment with fadraciclib, resulting in a rapid induction of apoptosis. In addition, RNA polymerase II (RNAPII)-driven transcription was suppressed, rendering a global gene suppression. Rapid induction of apoptosis was observed in primary AML cells after treatment with fadraciclib for 6–8 h. Twenty-four hours continuous treatment further increased efficacy of fadraciclib. Although preliminary results showed that AML cell lines harboring
KMT2A
rearrangement (
KMT2A
-r) are more sensitive to fadraciclib, we found that the drug can induce apoptosis and decrease MCL-1 expression in primary AML cells, regardless of
KMT2A
status. Importantly, the diversity of genetic mutations observed in primary AML patient samples was associated with variable response to fadraciclib, confirming the need for patient stratification to enable a more effective and personalized treatment approach. Synergistic activity was demonstrated when fadraciclib was combined with the BCL-2 inhibitor venetoclax, or the conventional chemotherapy agents, cytarabine, or azacitidine, with the combination of fadraciclib and azacitidine having the most favorable therapeutic window. In summary, these results highlight the potential of fadraciclib as a novel therapeutic approach for AML.