Combining three targeted drugs together can block drug resistance in bowel cancer patients, a new study* shows. Scientists writing in the journal Oncogene found that bowel cancer cells evolve resistance in response to two molecularly targeted cancer drugs through mutation of their targets – but using three drugs together kept resistance at bay.
The new study found that a triple attack could be effective in bowel cancer– and potentially many other tumour types– by overcoming cancer’s ability to adapt, evolve and evade the effects of treatment.
Scientists at The Institute of Cancer Research (ICR), funded by Cancer Research UK, examined 47 bowel cancer cells lines to help understand exactly how resistance to drugs arises as the cancer evolves to escape treatment. They 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 bowel cancer– the fourth most common cancer in the UK– cells often become resistant to targeted treatment through mutations that affect ‘on/off’ signalling molecules, causing them to be stuck in the ‘on’ or ‘off’ position.
In order to understand how cancer evolves to develop resistance, scientists exposed bowel cancer cells to increasing levels of two drugs which inhibit these ‘on/off’ switches.
These drugs were cobimetinib and pictilisib– the latter of which was discovered in a collaboration between the ICR and industry partners, and is now being used in clinical trials for several cancer types. At first the drugs worked together to stop cancer cells growing in almost all of the bowel cancer cell lines.
However, when one of the responsive cell lines was exposed to the drugs for a period of eight to 10 weeks, the cells developed resistance to the drug combination, resulting from a loss of or reduced sensitivity to one of the two drugs.
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.
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.
Combinations of targeted treatments that attack cancer in multiple ways at once have huge potential for preventing the disease from evolving resistance– using the same approach as in successful treatments for HIV and tuberculosis.
Further research is now required to assess the drug combination in animal studies. The researchers warned that care would need to be taken to monitor the tolerability of using the drugs simultaneously, in which case the dosing may need to be staggered to minimise side effects.
Study author Dr Paul Clarke, senior researcher in signal transduction and molecular pharmacology at the ICR, 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.”
*Clarke PA, Roe T, Swabey K, et al. Dissecting mechanisms of resistance to targeted drug combination therapy in human colorectal cancer. Oncogene 2019, DOI: 10.1038/s41388-019-0780-z