Transcriptional Silencing of MCL-1 Through Cyclin-Dependent Kinase Inhibition in Acute Myeloid Leukemia

Abstract

Acute myeloid leukemia (AML) is the most common adult acute leukemia. Survival remains poor, despite decades of scientific advances. Cytotoxic induction chemotherapy regimens are standard-of-care for most patients. Many investigations have highlighted the genomic heterogeneity of AML, and several new targeted therapeutic options have recently been approved. Additional novel therapies are showing promising clinical results and may rapidly transform the therapeutic landscape of AML. Despite the emerging clinical success of B-cell lymphoma (BCL)-2 targeting in AML and a large body of preclinical data supporting myeloid leukemia cell (MCL)-1 as an attractive therapeutic target for AML, MCL-1 targeting remains relatively unexplored, although novel MCL-1 inhibitors are under clinical investigation. Inhibitors of cyclin-dependent kinases (CDKs) involved in the regulation of transcription, CDK9 in particular, are being investigated in AML as a strategy to target MCL-1 indirectly. In this article, we review the basis for CDK inhibition in oncology with a focus on relevant preclinical mechanism-of-action studies of CDK9 inhibitors in the context of their therapeutic potential specifically in AML.

Ubiquitination and deubiquitination of MCL1 in cancer: deciphering chemoresistance mechanisms and providing potential therapeutic options

“…One alternative strategy to target MCL1 is by facilitating its transcriptional repression. CDK9 has an important role in regulating gene transcription and has become a potential therapeutic target in cancer treatment 108,109 . Inhibition of CDK9 triggers the suppression of short-lived transcripts and proteins, such as MCL1, to induce tumor cell death 110,111 , and is thus used in concert with BH3 mimetic drugs for cancer treatment 112 .…”

B-cell lymphoma-2 inhibition and resistance in acute myeloid leukemia

“…Alvocidib, aka flavopiridol, was the first of the CDK9 agents tested in combination with conventional chemotherapy[ 70 ]. A newer agent voruciclib that inhibits CDK9, 4, and 6 kinase diminishes transcription of MCL-1 downstream with better toxicity profile in comparison[ 71 ].…”

CDK9 as a Valuable Target in Cancer: From Natural Compounds Inhibitors to Current Treatment in Pediatric Soft Tissue Sarcomas

“…This crucial function and the evidence that transcriptional programs are dysregulated in cancer made CDK9 an attractive target for anti-cancer therapies. In agreement, modulation of CDK9 has been recently shown as a promising strategy to hamper the transcriptional machinery in tumors types that are strictly dependent on aberrant transcription from tumor-driver oncogenes (Tibes and Bogenberger, 2019;Chou et al, 2020).…”