Scientists at the Indian Association for the Cultivation of Science (IACS) in Kolkata have identified a novel therapeutic strategy to combat drug resistance in cancer by targeting two key proteins involved in DNA repair: Cyclin-dependent kinase 1 (CDK1) and Tyrosyl-DNA phosphodiesterase 1 (TDP1). The study, published in The EMBO Journal, suggests that inhibiting both CDK1 and TDP1 can synergistically enhance the effectiveness of existing Topoisomerase 1 (Top1) inhibitors, particularly in patients who have developed resistance to these drugs.
Overcoming Resistance to Top1 Inhibitors
Top1 inhibitors like camptothecin, topotecan, and irinotecan are commonly used chemotherapeutic agents. However, cancer cells often develop resistance by upregulating DNA repair mechanisms. The research team, led by Prof. Benu Brata Das, discovered that cancer cells activate TDP1, a DNA repair enzyme, to counteract the effects of Top1 inhibitors, allowing them to survive. This activation highlights a critical vulnerability that can be exploited therapeutically.
The Role of CDK1 and TDP1 in DNA Repair
The study elucidates the interplay between CDK1 and TDP1 during DNA repair. TDP1, known for repairing drug-induced trapped Top1 during the S phase of DNA replication, was found to be regulated by CDK1 during the mitotic phase. CDK1 phosphorylates TDP1, enhancing its ability to resolve Top1-DNA adducts. This phosphorylation event is crucial for efficient DNA repair during cell division, enabling cancer cells to withstand Top1-targeted chemotherapy.
Prof. Das explained, "Our work demonstrates that CDK1 directly regulates TDP1, aiding cancer cells in repairing DNA breaks caused by Top1 inhibitors. By targeting both CDK1 and TDP1, we can potentially overcome resistance and improve treatment effectiveness."
Potential for Combination Therapy
The researchers propose that combining CDK1 inhibitors, such as avotaciclib, alvocidib, roniciclib, riviciclib, and dinaciclib, with Top1 inhibitors could significantly enhance cancer cell killing. This combination disrupts DNA repair mechanisms and halts the cell cycle, making it more difficult for cancer cells to survive. The rationale is that inhibiting CDK1 induces chromosome instability, effectively targeting cancer cells that rely on TDP1-mediated DNA repair.
"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. He further emphasized that "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."
This research opens new avenues for developing combination therapies that target DNA repair mechanisms, offering a promising strategy to combat drug resistance and improve outcomes for cancer patients.
