Researchers at the Indian Association for the Cultivation of Science (IACS), Kolkata, have identified a potential new cancer treatment strategy by targeting a DNA repair enzyme called Tyrosyl-DNA phosphodiesterase 1 (TDP1). Their findings open the door to a novel combination therapy, offering hope for cancer patients resistant to current treatments.

The study, recently published in The EMBO Journal, reveals how activating TDP1 allows cancer cells to survive chemotherapy drugs that inhibit the enzyme Topoisomerase 1 (Top1), a key player in DNA replication and transcription. Existing drugs like Camptothecin, Topotecan, and Irinotecan target Top1, but cancer cells often develop resistance to these treatments, requiring alternative approaches.

Led by Prof. Benu Brata Das, the research team investigated how cancer cells repair DNA during cell division, particularly when exposed to chemotherapy that targets Top1. They discovered that two proteins—Cyclin-dependent kinase 1 (CDK1) and TDP1—play crucial roles in DNA repair and drug resistance.

Prof. Das and his colleagues found that CDK1, a regulatory enzyme active during cell division, enhances TDP1's ability to repair DNA damage caused by Top1 inhibitors. This process allows cancer cells to evade the effects of these drugs, leading to resistance. “Our work demonstrates that CDK1 directly regulates TDP1, aiding cancer cells in repairing DNA breaks caused by Top1 inhibitors,” said Prof. Das. “By targeting both CDK1 and TDP1, we can potentially overcome resistance and improve treatment effectiveness.”

The team's findings suggest that inhibiting CDK1 with drugs such as avotaciclib, alvocidib, roniciclib, riviciclib, and dinaciclib, combined with Top1 inhibitors, could significantly enhance the effectiveness of cancer treatments. By disrupting the DNA repair mechanisms that allow cancer cells to survive, this combination could offer a new avenue for precision medicine.

Prof. Das emphasized the significance of the discovery, explaining that the phosphorylation of TDP1 by CDK1 is essential for cancer cells to manage DNA damage during cell division. Inhibiting CDK1 could lead to chromosome instability in cancer cells, effectively halting their proliferation.

“Cancer cells often develop resistance to single-agent treatments,” Prof. Das said. “By using both CDK1 and Top1 inhibitors, we can more effectively target and eliminate cancer cells.”

As the researchers continue to explore the potential of this dual-target approach, animal model studies are underway to validate its effectiveness. If successful, this breakthrough could offer a new lifeline for patients with cancers that are resistant to existing therapies.