In News:

Scientists have identified a promising new target for cancer treatment by activating a DNA repair enzyme called TDP1. This approach suggests a combination therapy that could serve as a potential precision medicine for patients resistant to current treatments.

• Current Treatment Limitations:
  • Existing anticancer drugs (e.g., Camptothecin, Topotecan, Irinotecan) target Topoisomerase 1 (Top1), essential for DNA replication and transcription.
  • Cancer cells frequently develop resistance to these single-agent therapies, necessitating alternative treatment strategies.
• Research Insights:
  • Conducted by scientists at the Indian Association for the Cultivation of Science (IACS), Kolkata, under the Department of Science and Technology (DST).
  • The study focused on how cancer cells repair DNA during cell division and respond to chemotherapy targeting Top1.
• Key Findings:
  • The research, published in The EMBO Journal 2024, highlights two critical proteins:
    • Cyclin-dependent kinase 1 (CDK1)
    • Tyrosyl-DNA phosphodiesterase 1 (TDP1)
  • CDK1 regulates the DNA repair process, while TDP1 helps cancer cells survive by repairing drug-induced Top1 damage.
• Mechanism of Action:
  • TDP1 repairs Top1 that is trapped during the S phase of DNA replication.
  • The role of TDP1 during the mitotic phase was previously unknown; CDK1 phosphorylates TDP1, enhancing its repair capabilities.
  • Phosphorylation is crucial for efficient DNA repair, allowing cancer cells to withstand Top1-targeted chemotherapy.
• Potential for Combination Therapy:
  • Targeting both CDK1 and TDP1 could help overcome drug resistance and improve treatment efficacy.
  • Suggested use of CDK1 inhibitors (e.g., avotaciclib, alvocidib) alongside Top1 inhibitors may disrupt DNA repair and halt the cell cycle, increasing cancer cell mortality.
• Research Implications:
  • Phosphorylation of TDP1 by CDK1 is essential for managing DNA damage in cancer cells.
  • Inhibiting CDK1 may induce chromosome instability, effectively targeting cancer cells.
  • The combination of CDK1 and Top1 inhibitors aims to enhance cancer treatment effectiveness.
• Future Directions:
  • Identifying CDK1 and TDP1 as potential targets paves the way for developing new cancer therapies that inhibit DNA repair mechanisms.
  • Further studies using animal models are ongoing to validate this innovative approach for precision medicine in treating resistant cancers.