'Significant' new cancer drug resistance mechanism identified
Monday 26 November 2012
A key cause of drug resistance in cancer cells has been identified by European and US researchers.
The research team, led by scientists at the Netherlands Cancer Institute, also shows precisely how the resistance develops, and suggests how it can be overcome.
"We need to understand the mechanisms of drug resistance to effectively prevent it from occurring in the first place," said senior study author Professor Rene Bernards.
For many cancer patients, chemotherapy or newer targeted drugs can work in the short term, but tumours often evolve to evade their effects, and continue growing.
Such drug resistance is thought to be caused by cells within the tumour mutating to overcome the medication's effects, and researchers have been attempting to identify the precise way this happens.
The latest research, published in the journal Cell, suggests that a gene called MED12 becomes deactivated in a wide variety of different drug-resistant cancer types.
The team started out by investigating lung cancer cells that had become resistant to drugs targeting the ALK gene, which is hyperactive in around five in every hundred lung cancer patients.
They found that, in many cases, a second gene called MED12 had become deactivated - and this was causing drug resistance.
Further experiments, exploiting an online 'encyclopaedia' of cancer cell data, suggested that this wasn't limited to lung cancer cells with mutant ALK genes, but was a common feature of resistant cells from a wide range of cancer types, treated with several types of drug.
In a final step, the researchers showed the consequences of switching off MED12. It led to the activation of a process called TGF-beta signalling, causing the cells to continue to divide, even in the presence of cancer drugs.
Drugs that block TGF-beta signalling are already in development, and the researchers speculate that combining them with existing drugs could slow down - or even stop - drug resistance developing - a concept that needs testing in trials.
"We have shown that blocking this escape route restores sensitivity to the original drug, suggesting a way to treat patients that have undergone this type of drug resistance." Bernards concluded.
Dr Ultan McDermott, a Cancer Research UK-funded researcher based at the Wellcome Trust Sanger Institute in Cambridge, and who helped construct the database used by the Dutch team, called it a "really significant" finding.
"There's been an increasing recognition that understanding drug resistance in greater detail holds the key to better treatments," he said.
"This is the first time TGF-beta signalling has been linked to drug resistance in cancer, and the way this seems to be happening - via a process called the epithelial-mesenchymal transition - is also new and unexpected.
"But it's also proof that the technique the researchers used - knocking out individual genes in cells to find out exactly how drug resistance develops - is a powerful technology that holds huge promise for the future. It's unlikely that MED12's role would have been uncovered without this," he added.
The next step, said McDermott, was to work out how the finding could be translated into ways to improve things for patients in the future.
Copyright Press Association 2012
- Huang S., Hölzel M., Knijnenburg T., Schlicker A., Roepman P., McDermott U., Garnett M., Grernrum W., Sun C. & Prahallad A. & (2012). MED12 Controls the Response to Multiple Cancer Drugs through Regulation of TGF-β Receptor Signaling, Cell, 151 (5) 937-950. DOI: 10.1016/j.cell.2012.10.035
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