CDK12: A Potent Target and Biomarker for Human Cancer Therapy

Abstract

Cyclin-dependent kinases (CDKs) are a group of serine/threonine protein kinases and play crucial roles in various cellular processes by regulating cell cycle and gene transcription. Cyclin-dependent kinase 12 (CDK12) is an important transcription-associated CDK. It shows versatile roles in regulating gene transcription, RNA splicing, translation, DNA damage response (DDR), cell cycle progression and cell proliferation. Recently, increasing evidence demonstrates the important role of CDK12 in various human cancers, illustrating it as both a biomarker of cancer and a potential target for cancer therapy. Here, we summarize the current knowledge of CDK12, and review the research advances of CDK12′s biological functions, especially its role in human cancers and as a potential target and biomarker for cancer therapy.

Hyperactivation of MEK/ERK pathway by Ca2+/calmodulin‐dependent protein kinase kinase 2 promotes cellular proliferation by activating cyclin‐dependent kinases and minichromosome maintenance protein in gastric cancer cells

“…CDK1 has been identified as a clinically useful prognostic marker in non‐small cell lung cancer, colon cancer, and breast cancer 52–55 . Apart from CDK1 other CDKs like CDK12 and CDK13 are also deregulated in different cancer, including GC, 56–58 and are reported as therapeutic targets in Triple‐Negative Breast Cancer 59 …”

CDK13-Mediated Cell Cycle Disorder Promotes Tumorigenesis of High HMGA2 Expression Gastric Cancer

“…Because CDK12 and CDK13 have the identical conserved kinase domains and activating partner (cyclin K), CDK13 has been studied as the companionship of CDK12 from the beginning, and the most light has been shed on CDK12, veiling the real face of CDK13 (Greifenberg et al, 2016;Fan et al, 2020;Tadesse et al, 2021). Thus, the function and the mechanism of CDK12 have been comparatively clear; moreover, the inhibitor of CDK12 was invented and has already entered the clinical trials (Blazek et al, 2011;Dubbury et al, 2018;Liang et al, 2020). However, there is no specific inhibitor for CDK13 until THZ531, a selective CDK12/13 inhibitor, was found in 2016 (Zhang et al, 2016).…”

Dinaciclib, a Bimodal Agent Effective against Endometrial Cancer

“…The arguments for targeting CDKs including those targeted by dinaciclib (CDKs 1, 2, 5, 9, and 12) are well-established and compelling [ 9 , 55 , 56 ]. Pan-CDKis inhibit multiple CDKs and thus target multiple cellular processes simultaneously, suggesting that these agents could be broadly effective over a heterogenous genetic landscape, as was seen here, with consistent efficacy of dinaciclib across EC primary cells and cell lines.…”