Emerging target: CDK9 in MCL-1–dependent leukemic blasts
Preliminary clinical data suggest that CDK9 inhibition may have selective activity against leukemic blasts, possibly due to dependence on MCL-1. Therefore, MCL-1 regulation via inhibition of CDK9 may be a rational therapeutic strategy for some MCL-1–dependent hematologic malignancies.1-3
MCL-1 may drive blast survival
MCL-1 is a key anti-apoptotic member of the BCL-2 family of proteins.4 Dysregulated levels of MCL-1 may inhibit a cell’s natural death processes and promote aberrant blast survival and treatment resistance. Hematologic malignancies that persist via this mechanism are known as MCL-1 dependent.2,5-8
Target MCL-1–dependent blasts by inhibiting CDK9
CDK9 is a transcription-regulating protein that promotes the expression of MCL-1 by phosphorylating the carboxyl-terminal domain (CTD) of the largest subunit of RNA polymerase II, allowing transcription elongation of MCL-1 mRNA.2,9 Preclinical data have shown that MCL-1 can be downregulated through CDK9 inhibition. Therefore, MCL-1 regulation via inhibition of CDK9 may be a rational therapeutic strategy for some MCL-1–dependent hematologic malignancies.1-3
*The prevalence of MCL-1–dependent hematologic malignancies is being investigated.
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- Yin T, Lallena MJ, Kreklau EL, et al. A novel CDK9 inhibitor shows potent antitumor efficacy in preclinical hematologic tumor models. Mol Cancer Ther. 2014;13(6):1442-1456.
- Boffo S, Damato A, Alfano L, Giordano A. CDK9 inhibitors in acute myeloid leukemia. J Exp Clin Cancer Res. 2018;37(1):36.
- Kim W, Whatcott C, Siddiqui-Jain A, et al. The CDK9 inhibitor, alvocidib, potentiates the non-clinical activity of azacytidine or decitabine in an MCL-1-dependent fashion, supporting clinical efficacy of a decitabine and alvocitib combination. Blood. 2018;132(suppl 1):4355.
- Perciavalle RM, Opferman JT. Delving deeper: MCL-1's contributions to normal and cancer biology. Trends Cell Biol. 2013;23(1):22-29.
- Cassier PA, Castets M, Belhabri A, Vey N. Targeting apoptosis in acute myeloid leukaemia. Br J Cancer. 2017;117(8):1089-1098.
- Jilg S, Reidel V, Müller-Thomas C, et al. Blockade of BCL-2 proteins efficiently induces apoptosis in progenitor cells of high-risk myelodysplastic syndromes patients. Leukemia. 2016:30(1):112-123.
- McBride A, Houtmann S, Wilde L, et al. The role of inhibition of apoptosis in acute leukemias and myelodysplastic syndrome. Front Oncl. 2019;9:192.
- Reidel V, Kaushinger J, Hauch RT, et al. Selective inhibition of BCL-2 is a promising target in patients with high-risk myelodysplastic syndromes and adverse mutational profile. Oncotarget. 2018;9(25):17270-17281.
- Chen R, Keating MJ, Gandhi V, Plunkett W. Transcription inhibition by flavopiridol: mechanism of chronic lymphocytic leukemia cell death. Blood. 2005;106(7):2513-2519.