Samaan Lateef | New Delhi
Indian scientists have identified a potential breakthrough in cancer treatment by targeting a DNA repair enzyme called Tyrosyl-DNA phosphodiesterase 1 (TDP1), which could help overcome resistance to current therapies.
The discovery, made by researchers at the Indian Association for the Cultivation of Science (IACS), suggests that inhibiting both TDP1 and Cyclin-dependent kinase 1 (CDK1) could improve the effectiveness of existing cancer drugs.
The study, published in “The EMBO Journal”, reveals how cancer cells develop resistance to anticancer drugs like Camptothecin and Topotecan, which target the Topoisomerase 1 (Top1) enzyme, crucial for DNA replication. Cancer cells survive by activating TDP1 to repair DNA damage, rendering these treatments less effective.
Lead researcher Professor Benu Brata Das explained that their work demonstrates CDK1’s role in regulating TDP1 during cell division, enabling cancer cells to repair DNA damage and resist chemotherapy. “By targeting both CDK1 and TDP1, we can disrupt the DNA repair process and improve cancer cell killing,” said Das, who along with his team at IACS, an autonomous institute under India’s Department of Science and Technology (DST), found that by inhibiting both TDP1 and Cyclin-dependent kinase 1 (CDK1), cancer treatment can be significantly improved.
This research opens new possibilities for combination therapies, particularly for patients whose cancer has become resistant to current treatments.
Existing cancer drugs like Camptothecin, Topotecan, and Irinotecan target an enzyme essential for DNA replication and transcription, known as Topoisomerase 1 (Top1). However, cancer cells often develop resistance to these treatments by activating TDP1, which repairs DNA damage caused by the drugs, allowing the cells to survive.
“Our work demonstrates that CDK1 directly regulates TDP1, aiding cancer cells in repairing DNA breaks caused by Top1 inhibitors,” said Prof. Das, the study’s corresponding author. “By targeting both CDK1 and TDP1, we can potentially overcome resistance and improve treatment effectiveness.”
The study highlights the critical role of CDK1, a regulatory protein in the mitotic phase of cell division, which phosphorylates TDP1 and enhances its ability to repair drug-induced DNA damage. This phosphorylation event is key to the efficient DNA repair process that allows cancer cells to survive chemotherapy.
The researchers propose a combination therapy using CDK1 inhibitors, such as avotaciclib, alvocidib, roniciclib, riviciclib, and dinaciclib, alongside Top1 inhibitors to enhance the effectiveness of cancer treatments. “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,” Prof. Das added.
The research underscores the potential of this combination therapy in combating cancers that have developed resistance to single-agent treatments. “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,” Prof. Das emphasized.
The breakthrough opens a promising avenue for precision medicine, especially for treating cancers that are resistant to current therapies. Further studies using animal models are underway to validate the findings and explore their clinical applications.
