Researchers exploring cancer therapies are focusing on cyclin-dependent kinases, or CDKs, which regulate cell division and gene expression.
Targeting Transcriptional CDKs to Disrupt Cancer Cell Growth
Cancer is the second leading cause of death in Germany. In the search for new therapeutic approaches that target the uncontrolled growth of tumor cells, a class of enzymes known as cyclin-dependent kinases (CDKs) has come into focus. This is because this family of enzymes plays a fundamental role in gene expression and cell division.
Malignancies frequently alter gene expression, the process by which the cell’s genetic material is made usable. RNA polymerase II carries out the central step in this process, transcribing the information on the genetic material carrier, DNA, into messenger RNA, which serves as a blueprint for protein synthesis. When these regulatory mechanisms become disrupted and operate in an uncoordinated manner, cells can become malignant, leading to the development of cancer. Inhibiting transcription-regulating CDKs can reduce gene expression and also disrupt the processing of the resulting messenger RNA, offering a targeted way to affect tumor cells more effectively than healthy tissue.
Balancing Established CDK4 and CDK6 Inhibitors With Emerging Technologies
Aggressive tumor types such as leukemias, breast, lung, or ovarian cancer hold particular potential for such approaches. Four different active substances targeting the kinases CDK4 and CDK6 are used in the treatment of the HR+/HER2-negative breast cancer subtype.
“There are already four different active substances targeting the kinases CDK4 and CDK6 that are used in the treatment of the HR+/HER2-negative breast cancer subtype,”
Prof. Dr. Matthias Geyer of the Institute of Structural Biology at the UKB
“But their efficacy in prostate cancer is also currently being investigated in clinical trials.”
Prof. Dr. Matthias Geyer of the Institute of Structural Biology at the UKB
The overview was compiled by Prof. Matthias Geyer of the University Hospital Bonn and the University of Bonn in collaboration with Prof. Robert P. Fisher of the Icahn School of Medicine at Mount Sinai, New York. Prof. Geyer is a member of the Cluster of Excellence ImmunoSensation3 and the Transdisciplinary Research Area (TRA) Life & Health
at the University of Bonn, while Prof. Robert P. Fisher is from the Department of Oncological Sciences at the Icahn School of Medicine at Mount Sinai in New York. Beyond classic inhibitors, innovative technologies are presented, including so-called PROTACs and molecular glues
, which can specifically degrade disease-relevant proteins or rewire cellular signaling pathways. Researchers are also examining the possibility of combining such substances with existing therapies—such as immunotherapies or PARP inhibitors, which block DNA repair in tumor cells—to further increase efficacy.
Cell Cycle Checkpoints, DNA Repair, and Therapeutic Resistance
Cell cycle progression relies heavily on mitogenic factors that commence intracellular signaling cascades that activate CDK4 and CDK6, facilitating the progression from the G0 or G1 phase to the S phase, during which DNA replication transpires. CDKs and their cyclin partners also play crucial roles in transcriptional control and homologous recombination-mediated DNA repair tasks crucial for cancer development and treatment resistance.
For instance, CDK12 phosphorylates RNA polymerase II and regulates the expression of DNA damage response (DDR) genes, including BRCA1 and FANCD2. Lack of CDK12 or its suppression causes a homologous recombination deficit, which makes cancers more vulnerable to PARP inhibitors and other medications that cause DNA damage. Meanwhile, transcriptional CDKs such as CDK7 and CDK9 help cancer cells survive during genotoxic stress by controlling the expression of oncogenes and DNA damage response-related genes.
| CDK Target | Primary Cellular Role | Potential Therapeutic Strategy |
|---|---|---|
| CDK4 / CDK6 | G1/S phase progression, cell cycle control | Classic inhibitors, PROTACs, molecular glues |
| CDK12 / CDK13 | Transcription regulation, chromatin structure, DNA repair | Targeted suppression to induce homologous recombination deficit |
| CDK7 / CDK9 | RNA polymerase II phosphorylation, oncogene transcription | Transcriptional inhibition to combat DNA-damage resistance |
Overcoming Resistance Mechanisms and Side Effect Challenges
Despite therapeutic advancements, the authors emphasize the challenges. Because CDKs perform essential functions in healthy cells, new drugs must act with high precision so that these cells are largely spared, thereby minimizing side effects. Epigenetic mechanisms like DNA methylation and histone modifications—as well as stem cell control where CDKs influence cancer stem cell self-renewal, tumor start, spread, and recurrence—further complicate treatment by enabling drug resistance and tumor heterogeneity.
Opportunities to therapeutically influence the transcriptional machinery may also arise in other conditions, such as the inflammatory joint disease rheumatoid arthritis, as highlighted in the collaborative work published in Nature Reviews Drug Discovery.
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