A triple attack on bowel cancer

Three-pronged attack with targeted drugs can overcome drug resistance in bowel cancer

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A new study has shown that three targeted drugs combined can block drug resistance in bowel cancer patients. Researchers found that bowel cancer cells evolve resistance in response to two molecularly targeted cancer drugs through mutation of their targets – but using three drugs was enough to keep resistance at bay.
Patients often respond well to new targeted cancer drugs, only to later relapse as their cancers stop responding to treatment and start growing once again. But the new study found that a triple attack could be effective in bowel cancer – and potentially many other tumor types – by overcoming cancer’s ability to adapt, evolve and evade the effects of treatment. Scientists at The Institute of Cancer Research (ICR), London, examined 47 bowel cancer cells lines to help understand exactly how resistance to drugs arises as the cancer evolves to escape treatment. The study, funded by Cancer Research UK, was published in Oncogene yesterday.
According to study author Dr. Paul Clarke, senior researcher in Signal Transduction and Molecular Pharmacology at ICR, “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.”
Bowel cancer cells mutated and evolved to acquire resistance to treatment when grown under the selective pressure of two molecularly targeted cancer drugs. To overcome this resistance and prevent any further resistance developing, the researchers added a third drug – requiring cancer cells to evade three drugs at once in order to survive. In bowel cancer, cells often become resistant to targeted treatment through mutations that affect on/off signaling molecules, causing them to be stuck in the on or off position.
“Our study dissected out the process by which bowel cancer cells evolve to become drug resistant, and has applied the knowledge gained to the design of a new triple combination treatment. Further research is needed, but we think this triple combination of targeted drugs has the potential to help patients respond to treatment for much longer,” noted study co-author Professor Paul Workman, Chief Executive at ICR.
As the study states, “Combination treatment regimens have several advantages over monotherapy: they may increase antitumor effects within acceptable toxicity limits, are more likely to be effective against a heterogeneous tumor population and may delay or block the development of drug resistance. Here, we used a panel of human colorectal cancer cell lines to explore response to mono- and combination-therapies targeting MEK and PI3K. Initial sensitivity profiling work was followed up with a focused strategy using a single colorectal cancer cell line model to identify mechanisms of resistance. While the latter approach may not define the full spectrum of resistance in colorectal cancer, we did find resistance mechanisms, namely loss of PTEN and mutation of MEK1/2, that were previously reported in clinical resistance to MEK and PI3K inhibitors, thus validating the approach.”
In order to understand how cancer evolves, scientists exposed bowel cancer cells to increasing levels of cobimetinib and pictilisib which inhibit these on/off switches. At first, the drugs worked together to stop cancer cells growing in almost all of the bowel cancer cell lines. But 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 the bowel cancer cells were dependent on a group of molecules that regulate cell death for survival, called the BCL-2 family. When they exposed cells for several weeks to cobimetinib, pictilisib and a third drug called navitoclax, which inhibits molecules in the BCL-2 family, resistance was completely blocked.

“Overall, we clearly show that a combination treatment targeting the MEK- and PI3K-pathways is insufficient to block the acquisition of resistance in human colorectal cancer cell line models, but the addition of a third agent, a BCL2 inhibitor, is able to do this,” the article continues. “Importantly, the synergistic effect of the three-way combination was lost in cells with prior acquisition of resistance to one arm of the combination, suggesting that the triple therapy strategy is better suited to preventing the acquisition of resistance rather than overcoming existing intrinsic or acquired resistance from prior treatment.”
Combinations of targeted treatments 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 minimize side effects.
“These early data in cell lines suggest that taking advantage of existing drugs and combining them might help to prevent cancer drug resistance,” said Professor Charles Swanton, chief clinician at Cancer Research UK. “Further research in the lab and eventually clinical trials will help us find out if this is safe and effective for people with colorectal cancer.”

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