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Combining targeted cancer drugs is best when used to the max

Combining drugs that inhibit two signalling pathways critical to cancer growth could boost treatment outcomes for some types of cancer, but only when used together at maximum doses, a new study has found.

Scientists at The Institute of Cancer Research, London, showed that 100% inhibition of both the MEK and AKT pathways slowed down cell growth in 11 of 20 cancer cell lines they tested, compared with either MEK or AKT inhibition alone. 

However, combining the drugs in doses that led to less than full inhibition of either pathway was not as effective as using just one treatment. 

The findings have important implications for how clinical trials combining MEK and AKT inhibitors are conducted, and questions drug schedules recommended by continuous dosing which may only partially inhibit MEK and AKT signalling. 

In the future, intermittent drug scheduling to achieve full MEK/AKT inhibition could be a useful model for new trial designs.

The study, which was published in the journal Annals of Oncology, was funded by Cancer Research UK, with additional support from an Experimental Cancer Medicine Award and the NIHR Biomedical Research Centre at the ICR and The Royal Marsden. 

MEK and AKT are two proteins that are critical to how cancer cells grow and function. They form part of a complex network of signalling pathways that are used by genes commonly mutated in cancer. 

The proteins can be targeted by modern drug treatments that have shown promise clinically, but because of the way that MEK and AKT interact in our cells and the mixture of genetic mutations seen in human tumours, inhibiting one on its own is not enough to prevent tumour growth. 

Combining drugs to block both signalling mechanisms could be an effective way to treat cancer, but it can be difficult to use both drugs at high doses because of side-effects. 

ICR scientists combined an AKT inhibitor with a MEK inhibitor in 20 cancer cell lines with common cancer mutations and tested the effect inhibiting signalling using a range of concentrations of both drugs had on the combination’s ability to prevent cancer growth. 

They found that in 11 of the 20 cell lines tested, completely blocking both MEK and AKT prevented cell growth more fully than blocking either separately. 

And when they exposed the cells to drug combinations where both MEK inhibition and AKT inhibition was incomplete, they found that the treatment was better at preventing growth in just one of the cell lines from the 20 tested, compared with using either treatment alone. 

They also saw that cell growth in BRAF and PIK3CA mutations signal depended predominantly on signalling through MEK and AKT, respectively, but growth of cells with KRAS mutations often depend on both pathways, suggesting that combinations of MEK and AKT inhibitors are likely to be active in KRAS-driven cancers.

The findings show that some cancers with particular mutations responded better to incomplete inhibition of AKT and MEK than others, and that this should be factored into clinical trials testing combination treatments. 

Study leader Dr Udai Banerji, Cancer Research UK Senior Lecturer at the ICR and an honorary consultant at The Royal Marsden, said: “The ICR has led the field in AKT biology and drug development, with two drugs targeting AKT which were discovered in collaboration with the ICR that are currently being tested in the clinic, called AZD5363 and AT13148. It is important to understand how to maximise the chance of success of this class of agents for patients with cancer.

“This paper explores the biology behind delivering combinations of MEK and AKT inhibitors in a practical way, and is critical to planning clinical trials of these agents. It suggests that our current practice of submaximally inhibiting MEK and AKT through continuous drug schedules in combination trials are not ideal and we need to think of ways around this, possibly exploring intermittent schedules where it will be possible to inhibit MEK and AKT maximally.”
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