This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: More than 30 years after the direct connection was established between the molecular machinery controlling cell division and cancer, a new paper traces the evolution of cyclin-dependent kinase research and outlines the next generation of CDK-targeted therapies. Published in Molecular Medicine, the article, "Cyclin/CDK inhibition in cancer therapy: from small molecules and macrocycles to advanced drug delivery systems," provides a comprehensive analysis of established and emerging strategies for targeting cyclin-dependent kinases, or CDKs.
CDKs are enzymes that regulate cell-cycle progression, but their biological influence extends well beyond cell division. They also participate in gene transcription, DNA-damage responses, DNA repair, metabolism, immune regulation and cellular senescence. Their dysregulation is a defining feature of many malignancies, making them important but highly complex therapeutic targets.
The new publication carries particular historical significance for its senior and co-corresponding author, Antonio Giordano, M.D., Ph.D., founder and director of the Sbarro Health Research Organization (SHRO) and professor at Temple University. In 1989, Giordano was the first author of a landmark study published in Cell that provided one of the earliest direct experimental links between the cyclin/CDK machinery and oncogenic transformation. The researchers demonstrated that a cdc2-associated protein complex interacted with the adenovirus E1A oncoprotein in infected and transformed human cells.
The p60 component of that complex was subsequently identified as cyclin A. Five years later, in 1994, Giordano's laboratory at Temple University identified a previously unknown nuclear kinase, initially named PITALRE and now recognized as CDK9. The original study, published in the Proceedings of the National Academy of Sciences, showed that PITALRE was associated with kinase activity directed against the retinoblastoma protein.
CDK9 has since emerged as a crucial regulator of transcription, DNA-damage responses and cancer-cell survival, as well as an increasingly important target for anticancer therapy. "This review closes a scientific circle that began for me in 1989, when we helped demonstrate that the machinery controlling normal cell division could be directly connected to oncogenic transformation, and continued in 1994 with the identification of PITALRE, the kinase now known as CDK9," says Giordano, who also serves as director of the Sbarro Institute for Cancer Research and Molecular Medicine at Temple. "Today, we understand that cyclin-dependent kinases are not merely molecular switches driving cell proliferation.
They are central regulatory hubs connecting cell division with gene transcription, DNA repair, metabolism, immune responses and cellular senescence. CDK9, in particular, stands at the intersection of transcription, genome stability and cancer-cell survival," Giordano concludes. Several small-molecule CDK inhibitors have already been approved for cancer treatment, particularly drugs targeting CDK4 and CDK6.
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