In a promising development for cancer treatment, researchers have pinpointed a new target by activating a DNA repair enzyme known as Tyrosyl-DNA phosphodiesterase 1 (TDP1). This discovery, suggesting a combination therapy approach, could significantly benefit patients resistant to existing cancer treatments.

A team from the Indian Association for the Cultivation of Science (IACS) in Kolkata conducted the study, exploring how cancer cells repair DNA during cell division and their responses to chemotherapy aimed at the enzyme Topoisomerase 1 (Top1), a common cause of drug resistance. The findings were published in The EMBO Journal 2024.

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According to a Ministry of Science and Technology press note, the research highlights two crucial proteins: Cyclin-dependent kinase 1 (CDK1) and TDP1. Current anticancer drugs like Camptothecin, Topotecan, and Irinotecan target Top1, but cancer cells often develop resistance to these treatments, necessitating alternative therapeutic strategies.

Led by Prof. Benu Brata Das, the team found that cancer cells can survive existing therapies by activating TDP1, which helps repair DNA damage. Their investigation revealed the significant roles of CDK1 and TDP1 in regulating the DNA repair process, particularly in how cells cope with damage induced by Top1 inhibitors. Previously recognized primarily for its role during the S phase of DNA replication, TDP1’s function in the mitotic phase was less understood. The researchers discovered that CDK1, a critical kinase during mitosis, enhances TDP1’s ability to resolve drug-induced DNA damage by phosphorylating it.

“Our findings indicate that CDK1 directly regulates TDP1, aiding cancer cells in repairing DNA breaks caused by Top1 inhibitors,” explained Prof. Das. “Targeting both CDK1 and TDP1 could potentially overcome resistance and improve treatment outcomes.The study proposes that combining CDK1 inhibitors—like avotaciclib and dinaciclib—with Top1 inhibitors could enhance the effectiveness of cancer therapies by disrupting DNA repair mechanisms and impeding the cell cycle, making it harder for cancer cells to survive.

Prof. Das emphasized the importance of the phosphorylation process for DNA repair during cell division, stating, “By inhibiting CDK1, we can induce chromosome instability and more effectively target cancer cells.”

This research highlights CDK1 and TDP1 as vital targets for developing new cancer therapies aimed at inhibiting DNA repair, opening new avenues for treatment in patients facing drug resistance.