New Study Uncovers Dual Target for Overcoming Drug Resistance in Cancer Cells: CDK1 and TDP1

The breakthrough research was conducted by scientists at the Indian Association for the Cultivation of Science (IACS), Kolkata, an autonomous institute under the Department of Science and Technology (DST)

Scientists have discovered a promising new target for cancer treatment by activating a DNA repair enzyme called Tyrosyl-DNA phosphodiesterase 1 (TDP1), potentially paving the way for combination therapies that offer precision medicine, especially for cancers resistant to current treatments. The breakthrough research was conducted by scientists at the Indian Association for the Cultivation of Science (IACS), Kolkata, an autonomous institute under the Department of Science and Technology (DST).

Current anticancer drugs, such as Camptothecin, Topotecan, and Irinotecan, target Topoisomerase 1 (Top1), an enzyme essential for DNA replication and transcription. However, cancer cells often develop resistance to these single-agent therapies, requiring alternative treatment approaches. The IACS team focused on understanding how cancer cells repair DNA during cell division, particularly when treated with drugs that target Top1.

The study, published in The EMBO Journal 2024, highlights two critical proteins: Cyclin-dependent kinase 1 (CDK1) and TDP1, both of which play significant roles in cancer cell DNA repair. According to Prof. Benu Brata Das, who led the research, cancer cells counteract the effects of Top1 inhibitors by activating TDP1, allowing them to repair damaged DNA and survive.

DNA Repair Mechanism and Chemotherapy Resistance

Cancer cells leverage the DNA repair enzyme TDP1 to fix DNA breaks caused by Top1 inhibitors. The study revealed that CDK1, a key regulatory kinase during the mitotic phase of the cell cycle, phosphorylates TDP1, enhancing its ability to repair DNA. This phosphorylation is crucial for enabling cancer cells to survive Top1-targeted chemotherapy.

“Our work demonstrates that CDK1 directly regulates TDP1, aiding cancer cells in repairing DNA breaks caused by Top1 inhibitors,” Prof. Das explained. This insight suggests that targeting both CDK1 and TDP1 could provide a new treatment strategy for overcoming drug resistance.

Potential for Combination Therapy

The study proposes using CDK1 inhibitors, such as avotaciclib, alvocidib, roniciclib, riviciclib, and dinaciclib, alongside Top1 inhibitors to disrupt the DNA repair process and enhance cancer cell killing. By inhibiting CDK1, cancer cells are unable to properly manage DNA damage during cell division, leading to chromosome instability and making it more difficult for cancer cells to survive.

Prof. Das emphasized the potential of this combination therapy, stating, “Cancer cells often develop resistance to single-agent treatments. By using both CDK1 and Top1 inhibitors, we can more effectively target and eliminate cancer cells.”

Pathway to Precision Medicine

The identification of CDK1 as a key regulator and TDP1 as a repair enzyme opens up promising new avenues for developing cancer therapies that inhibit DNA repair mechanisms in cancer cells. This dual-target approach could be particularly beneficial for treating drug-resistant cancers.

Further studies using animal models are ongoing to validate the findings, but the research represents a major step towards precision medicine in cancer treatment. By targeting the DNA repair pathways that cancer cells rely on to survive, scientists hope to develop more effective therapies that could reshape the landscape of cancer treatment.

This breakthrough suggests that therapies which simultaneously block CDK1 and Top1 could offer a powerful new tool in the fight against cancer, potentially improving outcomes for patients with resistant forms of the disease.