Scientists have identified a promising new target for cancer treatment by activating a DNA repair enzyme called TDP1, suggesting a combination therapy which could be a potential precision medicine especially for those resistant to current cancer remedies.

Existing anticancer drugs like Camptothecin, Topotecan, and Irinotecan target an enzyme crucial for DNA replication and transcription called Topoisomerase 1 (Top1). Cancer cells often develop resistance to such single-agent treatments and hence require alternate therapy methods. 

In order to explore such alternative routes to treatment, Scientists at the Indian Association for the Cultivation of Science (IACS), Kolkata, an autonomous institute of the Department of Science and Technology (DST) probed how cancer cells repair DNA during cell division and respond to chemotherapy that targets the enzyme Top1, often leading to drug resistance.

The research published in The EMBO Journal 2024 highlights two key proteins --Cyclin-dependent kinase 1 (CDK1) and Tyrosyl-DNA phosphodiesterase 1 (TDP1).  The researchers led by Prof. Benu Brata Das found that cancer cells can counteract the effect of existing drugs by activating TDP1, a DNA repair enzyme, allowing them to survive.

While investigating how cancer cells repair DNA during cell division and respond to DNA damage induced by enzyme Topoisomerase 1 (Top1), the scientists discovered the critical roles of the proteins CDK1 and TDP1 that regulate the DNA repair process and repairs drug-induced trapped Top1 respectively.

TDP1, was known to be a dedicated enzyme that repairs drug-induced trapped Top1 during the S phase when the DNA replicates, but its role and regulation during the mitotic phase were previously unknown. CDK1, on the other hand, the key regulatory kinase in the mitotic phase, was found to regulate the DNA repair process by phosphorylating TDP1, which enhances its ability to resolve Top1-DNA adducts.

The scientists stressed that the phosphorylation event was crucial for efficient DNA repair during cell division, allowing 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,” explains Prof. Benu Brata Das, the study's corresponding author. “By targeting both CDK1 and TDP1, we can potentially overcome resistance and improve treatment effectiveness,” he added.

The study suggests that using CDK1 inhibitors—such as avotaciclib, alvocidib, roniciclib, riviciclib, and dinaciclib—alongside Top1 inhibitors could enhance cancer cell killing. This combination disrupts DNA repair mechanisms and halts the cell cycle, making it more difficult for cancer cells to survive.

 “We discovered that phosphorylation of TDP1 by CDK1 is essential for cancer cells to manage DNA damage during cell division. By inhibiting CDK1, we can induce chromosome instability, effectively targeting cancer cells,” said Prof Das.

 “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,” said Prof. Das emphasizing the potential of this combination therapy.

By identifying CDK1 as a key regulator and TDP1 as a repair enzyme, this research highlights both as potential targets for developing cancer therapies that inhibit DNA repair in cancer cells

This breakthrough points to a promising avenue for precision medicine in treating cancers, especially those resistant to current therapies. Further studies using animal models are ongoing to validate this approach.