Researchers have found a promising new target for cancer therapy, offering hope for patients who develop resistance to existing treatments. The scientists from the Indian Association for the Cultivation of Science (IACS), Kolkata, focused on a DNA repair enzyme, TDP1, which may be key to a new combination therapy.
Current cancer drugs like Camptothecin, Topotecan, and Irinotecan target the enzyme Topoisomerase 1 (Top1) crucial for DNA replication.
However, cancer cells often become resistant to these drugs, necessitating alternative approaches. The research, published in The EMBO Journal, explains how cancer cells repair DNA damage and develop resistance to these therapies.
The study revealed that two proteins, Cyclin-dependent kinase 1 (CDK1) and Tyrosyl-DNA phosphodiesterase 1 (TDP1), play critical roles in this repair process. Prof. Benu Brata Das and his team found that cancer cells activate TDP1 to counteract the effects of existing drugs, allowing them to survive. They discovered that CDK1 regulates TDP1 by phosphorylating it, which enhances TDP1’s ability to repair DNA damage and resist chemotherapy.
How does this therapy work?
TDP1 is essential for fixing DNA damage brought on by therapies such as Topoisomerase 1 (Top1) inhibitors, which are frequently used in chemotherapy. Through the repair of DNA breaks, the enzyme aids in the survival of cancer cells. According to recent research, blocking TDP1, perhaps in conjunction with CDK1 inhibitors, may stop cancer cells from mending themselves, increasing their susceptibility to therapy. Precision medicine may be made possible by this dual-target approach, which may also increase the efficacy of treatments and lessen cancer cell 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 researchers suggest that using CDK1 inhibitors, such as avotaciclib, alvocidib, roniciclib, riviciclib, and dinaciclib, along with Top1 inhibitors, could enhance the effectiveness of cancer treatments by disrupting DNA repair mechanisms. This combination could make it more difficult for cancer cells to survive.
Prof. Das explained, “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.”
