Using human breast cancer cells, a team of scientists at the Kolkata-based Indian Association for the Cultivation of Science (IACS) has discovered a new target for killing cancer cells, which can potentially lead to new therapies. This target is used by cancer cells to regulate DNA repair during cell division. Results of the study were published recently in The EMBO Journal.
The work sheds light on how cancer cells respond to topoisomerase 1-targeted chemotherapy, including how cancer cells sometimes develop resistance to treatment by using their intrinsic DNA repair toolbox. These insights could pave the way for precision medicine approaches for cancer patients.
Developing novel anti-cancer therapeutics may become possible through a combinatorial targeting of two key molecules — the CDK1 protein and the TDP1 enzyme. Present anti-cancer drugs — camptothecin, topotecan, and irinotecan — target a molecule (the enzyme topoisomerase 1 or Top1) involved in DNA metabolic processes like replication and transcription. The role of DNA topoisomerase 1 is critical for mitosis as it relaxes the DNA supercoil generated in the condensed chromosomes due to transcription.
“For the past decade at IACS, we have been investigating DNA repair pathways that provide resistance to camptothecin and its clinical derivatives,” says Dr. Benu Brata Das, Professor at the School of Biological Sciences at IACS and the corresponding author of the paper. “Our goal is to uncover new methods to target and eliminate these pathways through targeted or personalised chemotherapy, especially in breast and ovarian cancer. We are currently using mouse models to test the combination drug therapies using in vivo tumours.”
Treatment strategies
Top1, an enzyme found in all higher organisms, plays a crucial role in maintaining the 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 repair mechanisms using a protein called TDP1, which counteracts the effect of the drug.
Understanding the over-expression of various DNA repair proteins like Top1, TDP1 or CDK1 in cancers can provide critical insights into tumour biology. These insights can help in diagnosing and predicting cancer outcomes and guide the development of targeted and personalised treatment strategies. Knowing these biomarkers is essential for advancing cancer therapy, understanding resistance mechanisms, and improving patient outcomes, says Dr. Das.
The researchers at IACS have identified a key DNA repair protein — TDP1 — which plays a role in repairing the DNA damage in cancer cells. Their study shows that cells switch their repair tools depending on the stage of the cell cycle and the presence of a drug called camptothecin that is used in chemotherapy. They discovered that a specific change (phosphorylation) in TDP1 helps remove the TDP1 from the chromosomes during cell division. This finding is important because it helps explain how cells accurately divide and how problems in this process can lead to cancer.
The study suggests that targeting another protein (CDK1) can disrupt the Top1-mediated DNA damage-associated repair process, potentially killing cancer cells by causing chromosomal instability and stopping the cell division. “We discover a new mechanism where we show CDK1 directly regulates TDP1 through chemical fine tuning to repair DNA breaks generated by camptothecin, during mitosis thus offering resistance to chemotherapy,” says Srijita Paul Chowdhuri, the first author of the paper.
Shows promise
CDK1 inhibitors — avotaciclib, 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. Combining CDK1 inhibitors with Top1 inhibitors may have a powerful effect on cancer cells, the study finds. While Top1 inhibitors cause DNA damage, the CDK1 inhibitors prevent the repair of this damaged DNA or stop the cell cycle. This combination makes it very hard for cancer cells to survive, and can enhance 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 the cell cycle regulation. By using both Top1 and CDK1 inhibitors together, this resistance can be overcome, making it less likely for cancer cells to evade treatment,” says Dr. Das.
“Since the rate of proliferation is higher in the case of cancer cells, there are higher chances of the combination drug being taken up by cancer cells,” says Dr. Das. “The personalised approach of combinatorial chemotherapy will effectively kill cancer cells bypassing induced chemoresistance. More studies are needed to confirm the lab results,” he says.
Though the study was carried out in human breast cancer cells, the CDK1 inhibitors in combination with Top1 inhibitors can have additional benefits for patients suffering from other cancers, such as ovarian, colorectal, and small cell lung cancers (SCLC); small cell lung cancers are strongly associated with tobacco smoking.
