Scientists discover key enzyme to overcome cancer drug resistance
Researchers from the Indian Association for the Cultivation of Science (IACS) have made a significant breakthrough in cancer therapy by identifying a new therapeutic target: the DNA repair enzyme Tyrosyl-DNA phosphodiesterase 1 (TDP1). This discovery could lead to more effective treatment options for patients resistant to current anticancer drugs.
Current therapies like Camptothecin, Topotecan, and Irinotecan target the enzyme Topoisomerase 1 (Top1), crucial for DNA replication. However, cancer cells frequently develop resistance to these treatments, prompting scientists to seek alternative strategies.
Published in the *EMBO Journal* (2024), the study led by Prof. Benu Brata Das emphasizes the roles of two key proteins: Cyclin-dependent kinase 1 (CDK1) and TDP1. The researchers found that cancer cells can evade the effects of Top1 inhibitors by activating TDP1, which facilitates DNA repair during cell division, allowing continued proliferation despite chemotherapy.
The study highlights CDK1’s critical function in this process, revealing that it phosphorylates TDP1 to enhance its DNA repair capabilities. This phosphorylation is vital for cancer cell survival under Top1-targeted therapies.
“Our findings demonstrate that CDK1 directly regulates TDP1, enabling cancer cells to manage DNA damage caused by Top1 inhibitors,” said Prof. Das. “By targeting both CDK1 and TDP1, we can potentially overcome drug resistance and improve treatment outcomes.”
The researchers propose that combining CDK1 inhibitors—such as avotaciclib, alvocidib, and dinaciclib—with Top1 inhibitors could disrupt cancer cells’ DNA repair mechanisms, increasing their susceptibility to treatment.
Prof. Das elaborated, “Inhibiting CDK1 could induce chromosome instability, making it harder for cancer cells to survive.”
This innovative approach paves the way for precision medicine strategies, particularly for cancers resistant to conventional therapies. Further studies using animal models are planned to validate the effectiveness of this dual-target strategy and its potential for clinical application.
