New cancer therapy target can help patients overcome resistance to current treatments
Scientists have identified a
promising new target for cancer treatment by activating a DNA repair enzyme
called TDP1, suggesting a combination therapy which could be a potential
precision medicine especially for those resistant to current cancer remedies.
Existing anticancer drugs like Camptothecin, Topotecan,
and Irinotecan target an enzyme crucial for DNA replication and transcription
called Topoisomerase 1 (Top1). Cancer cells often develop resistance to such
single-agent treatments and hence require alternate therapy methods.
In order to explore such alternative routes to treatment,
scientists at the Indian Association for the Cultivation of Science (IACS),
Kolkata, an autonomous institute of the Department of Science and Technology
(DST) probed how cancer cells repair DNA during cell division and respond to
chemotherapy that targets the enzyme Top1, often leading to drug resistance.
The research published in The
EMBO Journal 2024 highlights two key proteins -- Cyclin-dependent
kinase 1 (CDK1) and Tyrosyl-DNA phosphodiesterase 1 (TDP1). The researchers led
by Prof Benu Brata Das found that cancer cells can counteract the effect of
existing drugs by activating TDP1, a DNA repair enzyme, allowing them to
survive.
While investigating how cancer cells repair DNA during
cell division and respond to DNA damage induced by enzyme Topoisomerase 1
(Top1), the scientists discovered the critical roles of the proteins CDK1 and
TDP1 that regulate the DNA repair process and repairs drug-induced trapped Top1
respectively.
The TDP1, was known to be a dedicated enzyme that repairs
drug-induced trapped Top1 during the S phase when the DNA replicates, but its
role and regulation during the mitotic phase were previously unknown. CDK1, on
the other hand, the key regulatory kinase in the mitotic phase, was found to
regulate the DNA repair process by phosphorylating TDP1, which enhances its
ability to resolve Top1-DNA adducts.
The scientists stressed that the phosphorylation event
was crucial for efficient DNA repair during cell division, allowing cancer
cells to survive Top1-targeted chemotherapy.
“Our work demonstrates that CDK1 directly regulates TDP1,
aiding cancer cells in repairing DNA breaks caused by Top1 inhibitors,”
explains Prof Benu Brata Das, the study's corresponding author. “By targeting
both CDK1 and TDP1, we can potentially overcome resistance and improve
treatment effectiveness,” he added.
The study suggests that using CDK1 inhibitors — such as
avotaciclib, alvocidib, roniciclib, riviciclib, and dinaciclib — alongside Top1
inhibitors could enhance cancer cell killing. This combination disrupts DNA
repair mechanisms and halts the cell cycle, making it more difficult for cancer
cells to survive.
“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.
“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,” said Prof Das emphasising the
potential of this combination therapy.
By identifying CDK1 as a key regulator and TDP1 as a
repair enzyme, this research highlights both as potential targets for
developing cancer therapies that inhibit DNA repair in cancer cells
This breakthrough points to a promising avenue for
precision medicine in treating cancers, especially those resistant to current
therapies. Further studies using animal models are ongoing to validate this
approach.