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A team of scientists from the Kolkata-based Indian Association for the Cultivation of Science (IACS) has discovered a new target to kill cancer cells using human breast cancer cells, which could potentially lead to new treatments. This target is used by cancer cells to regulate DNA repair during cell division. The results of the study were published recently EMBO Journal.
This research sheds light on how cancer cells respond to topoisomerase 1-targeted chemotherapy, including how cancer cells sometimes develop resistance to the treatment by using their internal DNA repair toolbox. These insights could pave the way for precision medicine approaches for cancer patients.
It may be possible to develop novel anti-cancer treatments through the combined targeting of two key molecules – the CDK1 protein and the TDP1 enzyme. Current anti-cancer drugs – camptothecin, topotecan and irinotecan – target a molecule (the enzyme topoisomerase 1 or Top1) involved in DNA metabolic processes such as replication and transcription. The role of DNA topoisomerase 1 is critical for mitosis as it relaxes DNA supercoils generated in condensed chromosomes due to transcription.
“For the past decade, at IACS, we have been investigating the DNA repair pathways that confer resistance to camptothecin and its clinical derivatives,” says Dr. Benu Brata Das, Professor at the School of Biological Sciences at IACS and corresponding author of the paper. “Our goal is to uncover new ways to target and eliminate these pathways through targeted or personalized chemotherapy, especially in breast and ovarian cancer. We are currently using mouse models to test combination drug therapies in living condition Tumor.”
Treatment Strategies
Top1, an enzyme found in all higher organisms, plays a key role in maintaining DNA structure during replication and transcription. Drugs that target Top1 disrupt its activity, leading to the death of many cells, including cancer cells. However, cancer cells can activate a repair mechanism using a protein called TDP1, which counteracts the drug’s effect.
Understanding the over-expression of various DNA repair proteins such as Top1, TDP1 or CDK1 in cancer can provide important insights into tumour biology. These insights can help diagnose and predict cancer outcomes and guide the development of targeted and personalised treatment strategies. Knowing these biomarkers is essential to advance cancer therapy, understand resistance mechanisms and improve patient outcomes, says Dr Das.
IACS researchers have identified a key DNA repair protein – TDP1 – that plays a role in repairing DNA damage in cancer cells. Their study shows that cells change their repair tools depending on the stage of the cell cycle and the presence of a drug called camptothecin, used in chemotherapy. They found that a specific change (phosphorylation) in TDP1 helps remove TDP1 from chromosomes during cell division. This discovery is important because it helps explain how cells divide precisely and how problems in this process can lead to cancer.
The study shows that targeting another protein (CDK1) can inhibit the repair process associated with Top1-mediated DNA damage, potentially killing cancer cells by causing chromosomal instability and preventing cell division. “We have discovered a new mechanism where we show that CDK1 directly regulates TDP1 through chemical fine-tuning to repair DNA breaks generated by camptothecin during mitosis, thus conferring resistance to chemotherapy,” says Sreejitha Paul Chowdhury, first author of the paper.
is promising
CDK1 inhibitors – evotaciclib, alvocidib, roniciclib, riviciclib and dinaciclib – are currently in various stages of clinical trials. These inhibitors can be used alone or in combination with other DNA-damaging agents. Studies have found that combining CDK1 inhibitors with Top1 inhibitors can have powerful effects on cancer cells. While Top1 inhibitors damage DNA, CDK1 inhibitors prevent the repair of this damaged DNA or stop the cell cycle. This combination makes it much harder for cancer cells to survive, and can increase the overall effectiveness of the treatment by targeting different aspects of the cell cycle and DNA replication.
“Cancer cells often develop resistance to single-agent therapies through various mechanisms, such as improved DNA repair pathways or changes in cell cycle regulation. By using Top1 and CDK1 inhibitors together, this resistance can be overcome, reducing the chance of cancer cells surviving treatment,” says Dr. Das.
“Since the rate of proliferation is high in case of cancer cells, the combination drug is more likely to be taken up by cancer cells,” says Dr Das. “The personalised approach of combinatorial chemotherapy will effectively kill cancer cells while bypassing induced chemoresistance. More studies are needed to confirm the laboratory results,” he adds.
Although this study was conducted on human breast cancer cells, taking CDK1 inhibitors in combination with Top1 inhibitors may have additional benefits for patients with other cancers, such as ovarian, colorectal, and small cell lung cancer (SCLC); small cell lung cancer is closely linked to tobacco smoking.
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