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Cancer cells limit DNA repair to overcome treatment

11 November 2019
Appeared in BioNews 1023

Colorectal cancer (CRC) cells increase the rate of mutations and impair DNA repair in their genomes to become more resistant to targeted therapies, a new study suggests.

It is already known that bacteria improve their chances of resistance to antibiotics by increasing the number of genomic mutations. The study now shows human CRC cells behave in the same way, and understanding this may help improve treatment approaches.

'The knowledge that cancer cells under therapeutic stress downregulate key effectors of the DNA repair machinery…exposes a vulnerability that could be clinically exploited,' said senior author Professor Alberto Bardelli, a cancer researcher at the Candiolo Cancer Institute and the University of Torino, Italy.

In the study, researchers based in Italy and the USA wanted to shed greater light on secondary resistance - a phenomenon that occurs when a targeted treatment is effective only for a short period of time against cancer cells before they develop resistant and start to grow again.

'Even in the best scenario, when the right drug is given to the right patient, even after great clinical response, the disease inevitably comes back. Sometimes it's even more aggressive than at the beginning,' said Dr Mariangela Russo, study first author, at the Candiolo Cancer Institute.

To understand better how secondary resistance develops, gene expression and other molecular features were monitored in CRC cell lines treated with the targeted cancer inhibitors cetuximab and dabrafenib. Although most cells died after 96 hours of treatment, a small number of drug-tolerant CRC cells survived for two weeks of treatment, and became permanently resistant after long-term exposure. 

These cells were found to have a greater predisposition to mutations and impaired DNA repair processes. Similar results were also observed in patient tumour samples that were subjected to targeted therapy.

Until now, drug resistance was only thought to arise due to the expansion of a small group of naturally resistant cells. The team now suspects that treatment resistance might occur as cancer cells limit the repair of new mutations, similar to bacterial resistance to antibiotics.

'This study provides compelling new data that challenge the way we think about how targeted treatment elicits resistance responses in colorectal cancers,' Professor Elaine Mardis at Ohio State University in Columbus, Ohio, who was not involved in the study, told The Scientist.

'The reported results set the stage for testing their extensibility in other cancer types, with other targeted therapies, and in preclinical models,' she said.

It will now be important to understand how cells adapt during treatment. Speaking to The Scientist, Dr Russo said: 'Finding the mechanism would allow [us] to eventually find new druggable hits,' opening up 'the possibility to stop or delay this adaptive mutability and therefore delay the onset of secondary resistance.'

The study was published in Science.

Adaptive mutability of colorectal cancers in response to targeted therapies
Science |  7 November 2019
Cancer Cells Increase DNA Mutations to Evade Treatment
The Scientist |  7 November 2019
Colorectal Cancers Dial up Mutability in Response to Targeted Treatments
Genomeweb |  7 November 2019
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