Transcription-Associated Cyclin-Dependent Kinases as Targets and Biomarkers for Cancer Therapy

Abstract

Drugs targeting the cell cycle-regulatory cyclin-dependent kinase (CDK) 4 and 6 have been approved for the treatment of hormone receptor-positive breast cancer, and inhibitors targeting other cell-cycle CDKs are currently in clinical trials. Another class of CDKs, the transcription-associated CDKs, including CDK7, CDK8, CDK9, CDK12 and CDK13, are critical regulators of gene expression. Recent evidence suggests several novel functions of these CDKs, including regulation of epigenetic modifi cations, intronic polyadenylation, DNA-damage responses, and genomic stability. Here, we summarize our current understanding of the transcriptional CDKs, their utility as biomarkers, and their potential as therapeutic targets.Signifi cance: CDK inhibitors targeting CDK4 and CDK6 have been approved in hormone receptor-positive breast cancer, and inhibitors targeting other cell-cycle CDKs are currently in clinical trials. Several studies now point to potential therapeutic opportunities by inhibiting the transcription-associated CDKs as well as therapeutic vulnerabilities with PARP inhibitors and immunotherapy in tumors defi cient in these CDKs.

A PP2A-Integrator complex fine-tunes transcription by opposing CDK9

“…Targeting of CDK9 can be therapeutically efficacious in pre-clinical models of MLLrearranged leukemia (Baker et al, 2016) and various other hematopoietic malignancies (Gregory et al, 2015), and CDK9i have progressed to clinical trials (Chou et al, 2020).…”

“…The recognition that perturbation of core-transcriptional components can fundamentally drive oncogenesis in a variety of cancers has spurred the development of small-molecule inhibitors targeting this process. Indeed, numerous CDK9 inhibitors have demonstrated promising results in pre-clinical studies (Chou et al, 2020). The recent development of PP2A agonists (Clark and Ohlmeyer, 2019) provided the opportunity to explore the molecular and therapeutic synergy between these compounds and CDK9i in MLL-rearranged leukemias where aberrant recruitment of the SEC fuels tumor initiation and progression (Luo et al, 2012).…”

Evaluation of the TRIP13 level in breast cancer and insights into potential molecular pathways

“…1). Now, drugs targeting the cell cycle-regulatory CDK 4 and 6 have been approved for the treatment of breast cancer, and inhibitors targeting other CDKs are in clinical trials recently [39]. These targets can be incorporated into the comprehensive treatment of BC.…”

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

“…The cyclin-dependent kinases (CDKs) family includes two main subgroups of kinases, those that mainly regulate cell cycle progression (including CDK1, CDK2, and CDK4/6) and those that control transcriptional processes (including CDK7, CDK8, CDK9, CDK12, and CDK13) (Roskoski, 2019;Chou et al, 2020). For some of the remaining CDKs the functions are still debated and/or under study.…”

“…The CDKs activity depends on specific regulatory cyclins subunits (29 cyclins in humans) with which CDKs form heterodimers (Malumbres, 2014). While levels of cell cycle-associated CDKs do not change during the different phases of cell cycle progression, those of their cyclin partners oscillate in a proteasomal-dependent manner thus timely activating selected CDKs (Malumbres, 2014;Chou et al, 2020).…”