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And researchers say that combined therapy could also attack other cancers
Mark Gould
Monday, March 25, 2019
A new study * shows that the combination of three targeted drugs can block drug resistance in patients with bowel cancer. Scientists writing in the newspaper oncogenic found that gut cancer cells developed resistance in response to two molecularly targeted anticancer drugs by mutating their targets – but that the simultaneous use of three drugs maintained resistance at bay.
The new study showed that a triple attack could be effective in bowel cancer – and potentially in other types of tumors – by overcoming cancer's ability to adapt, evolve and avoid the effects of cancer. treatment.
Scientists at the Cancer Institute (ICR), funded by Cancer Research UK, have examined 47 colon cancer cell lines to better understand how drug resistance develops as cancer evolves to escape treatment. They found that cancer cells in the intestine mutated and evolved to acquire resistance to treatment when grown under the selective pressure of two molecularly targeted anticancer drugs.
In order to overcome this resistance and prevent further resistance from developing, the researchers added a third drug – relegating the bar too high for cancer cells by forcing them to escape three different drugs at the same time to survive.
In cancer of the gut, the fourth most common cancer in the UK, cells often become resistant to targeted therapies through mutations affecting the signaling molecules "on / off", which blocks them in position " on "or" off ".
In order to understand how cancer is evolving to develop resistance, scientists have exposed the cancer cells of the gut to increasing rates of two drugs inhibiting these "on / off" switches.
These drugs were cobimetinib and pictilisib. This latest product was discovered during a collaboration between the ICR and industry partners. It is currently used in clinical trials involving several types of cancer. In the beginning, the drugs worked together to prevent cancer cells from proliferating in almost all the cancer cell lines of the intestine.
However, when one of the sensitive cell lines was exposed to drugs for a period of eight to ten weeks, the cells developed resistance to the combination of drugs, resulting in a loss or failure. a decrease in sensitivity to one of the two drugs.
The researchers found that cancer cells in the gut depended on a group of molecules called the BCL-2 family for their survival, which regulate cell death.
When they exposed cells for several weeks to a triple combination of cobimetinib, pictilisib and a third drug called navitoclax, which inhibits the molecules of the BCL-2 family, the emergence of ## EQU1 ## 39, resistance was completely blocked.
Combinations of targeted treatments that attack cancer in multiple ways at once have enormous potential to prevent the disease from developing, using the same approach as for effective treatments for HIV and TB.
Additional research is now needed to evaluate the combination of drugs in animal studies. The researchers warned that care should be taken to monitor the tolerance of simultaneous use of drugs, in which case it may be necessary to stagger the dosage to minimize side effects.
The author of the study, Dr. Paul Clarke, lead researcher in signal transduction and molecular pharmacology at the ICR, said, "Our study shows that it is possible to Use multiple targeted drugs together to overcome cancer drug resistance, as in other diseases such as HIV.
"At the ICR, we want to use the principles of evolutionary biology to understand how cancer can evolve over time and adapt to treatment – and what we can do to prevent this resistance from developing. We have shown that a three-pronged attack can be effective against cancer cells in the intestine by blocking their various escape routes from treatment. The research is still in its infancy, but in principle, targeted drug combinations could be just as effective against many other types of cancer. "
* Clarke PA, Roe T, Swabey K, et al. Mechanisms of dissection of resistance to a targeted drug combination in human colorectal cancer. Oncogene 2019, DOI: 10.1038 / s41388-019-0780-z
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