Cancer cells can turn on error-prone DNA copy pathways to adapt to cancer treatment in much the same way as bacteria develop antibiotic resistance, new research has revealed.
The process is known as stress-induced mutagenesis and can lead to drug resistance, according to a team led by David Thomas from Australia’s Garvan Institute of Medical Research.
Writing in the journal Science, they say a range of cancers, including melanoma, pancreatic cancer, sarcomas and breast cancer, have the ability to generate a high number of errors when they copy their DNA when exposed to cancer treatments.
“Resistance to treatment is arguably the major issue facing patients with advanced cancers, for whom even effective treatments ultimately fail,” Thomas notes.
Researchers have long known, he says, that cancer cells accumulate genetic variations that make it possible for them to evade treatment, but not how this happens.
With colleagues from Australia, France and Italy he began to investigate by analysing biopsy samples from cancer patients before and after they were treated with targeted therapies, which block the growth of cancer by interfering with molecules needed for tumour growth.
They were surprised to discover that the “after” cells showed much higher levels of DNA damage, even when the treatments did not directly damage DNA.
To pinpoint the underlying mechanisms, they carried out a large-scale screen to silence every gene in cancer cells individually, looking to identify the specific pathways contributing to drug resistance. And they found something unusual with the gene for MTOR.
“MTOR is a sensor protein that tells normal cells to stop growing because there is a stress in the environment, but we found that in the presence of a cancer treatment, MTOR signalling allowed cancer cells to change expression of genes involved in DNA repair and replication; for example shifting from high-fidelity polymerases, the enzymes that copy DNA, to production of error-prone polymerases,” says Garvan’s Arcadi Cipponi, the study’s first author.
“This resulted in more genetic variation, ultimately fuelling resistance to treatment.”
The shift to low-fidelity DNA repair and replication was temporary; once cancer cells acquired resistance to a cancer treatment, they reactivated high-fidelity pathways.
“Genomic instability can itself be harmful to cells, which is why some of our chemotherapies and therapeutic radiation work,” Cipponi says.
“We found that once cancer cells had developed resistance to a treatment, they switched back to high-fidelity DNA polymerases to ensure the cells that had evolved resistance to treatment could survive.”
The researchers suggest that combining conventional targeted cancer therapy with drugs that target DNA repair mechanisms may lead to more effective therapeutic strategies.
They report that in a proof-of-principle test in a mouse model they were able to reduce pancreatic cancer growth by almost 60% over 30 days, compared to using a cancer treatment alone.
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