Scientists have identified a promising new target for cancer treatment by activating a DNA repair enzyme called TDP1, offering hope to patients who have developed resistance to existing therapies. The discovery, made by researchers at the Indian Association for the Cultivation of Science (IACS) in Kolkata, suggests a combination therapy approach that could be a breakthrough in precision medicine for cancer treatment.

The study, published in The EMBO Journal, highlights how cancer cells often develop resistance to drugs that target the enzyme Topoisomerase 1 (Top1), a crucial component in DNA replication and transcription. Common cancer drugs like Camptothecin, Topotecan, and Irinotecan target this enzyme, but many cancer cells adapt and survive, leading to treatment failure.

Led by Prof. Benu Brata Das, the research focused on two key proteins—Cyclin-dependent kinase 1 (CDK1) and Tyrosyl-DNA phosphodiesterase 1 (TDP1)—which play vital roles in how cancer cells repair DNA during cell division and respond to chemotherapy. The study found that cancer cells activate TDP1, allowing them to repair DNA damage caused by Top1 inhibitors, making them resistant to these treatments.

“Our work shows that CDK1 directly regulates TDP1, helping cancer cells repair DNA breaks caused by Top1-targeted drugs,” said Prof. Das. The team discovered that CDK1 phosphorylates TDP1, enhancing its DNA repair ability during the cell division process, specifically in the mitotic phase. This phosphorylation event is crucial for the survival of cancer cells during chemotherapy.

The researchers suggest that combining CDK1 inhibitors—such as avotaciclib, alvocidib, and dinaciclib—with Top1 inhibitors could enhance the effectiveness of cancer therapies by disrupting DNA repair mechanisms. This combination could make it more difficult for cancer cells to survive and overcome drug resistance.

“We found that inhibiting CDK1 leads to chromosome instability, effectively targeting cancer cells and preventing them from managing DNA damage during cell division,” added Prof. Das.

This research offers a new potential pathway for developing precision cancer therapies, particularly for those patients who have become resistant to current treatments. Further studies using animal models are underway to validate the findings and explore their effectiveness in clinical applications.

The breakthrough paves the way for a new era in cancer treatment, providing hope for more effective strategies to combat drug-resistant cancers and improve patient outcomes.