Combining three targeted drugs together could help block drug resistance in bowel cancer patients, as bowel cancer cells evolve resistance in response to two molecularly targeted cancer drugs through mutation of their targets – but using three drugs together has been found to be enough to keep resistance at bay. The study - conducted by scientists at The Institute of Cancer Research, London - is published in Oncogene and was funded by Cancer Research UK.
The scientists examined 47 bowel cancer cells lines to help understand the exactly how resistance to drugs arises as the cancer evolves to escape treatment, and found that bowel cancer cells mutated and evolved to acquire resistance to treatment when grown under the selective pressure of two molecularly targeted cancer drugs.
In order to overcome this resistance and prevent any further resistance developing, the researchers added in a third drug – raising the bar too high for cancer cells by requiring them to be able to evade three different drugs at once in order to survive.
In order to understand how cancer evolves to develop resistance, scientists exposed bowel cancer cells to increasing levels of cobimetinib and pictilisib – the latter of which was discovered in a collaboration between The Institute of Cancer Research (ICR) and industry partners, and is now being used in clinical trials for several cancer types.
The researchers noticed that the bowel cancer cells were dependent on a group of molecules called the BCL-2 family for survival – which regulate cell death, but when they exposed cells for several weeks to a triple combination of cobimetinib, pictilisib and a third drug called navitoclax which inhibits molecules in the BCL-2 family, the emergence of resistance was completely blocked.
Study author Dr Paul Clarke, senior researcher in Signal Transduction and Molecular Pharmacology at The Institute of Cancer Research, London, said: “Our study shows the potential to use multiple targeted drugs together to overcome drug resistance in cancer, just as occurs in other diseases like HIV.
“At the ICR, we are interested in using the principles of evolutionary biology to understand how cancer can change 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 bowel cancer cells by blocking off their various escape routes from treatment.
“The research is still at a fairly early stage, but in principle combinations of targeted drugs could be similarly effective against many other cancer types.”