Scientists have discovered that a key cancer protein can promote the survival of cancer cells – even when targeted by drugs designed to block its main function.
The AKT protein, part of one of the most important signalling systems in cancer, was known to transmit survival signals to the cancer cell, but until now it had been believed to signal through a process called phosphorylation.
But the study led by scientists from The Institute of Cancer Research, London, and Memorial Sloan-Kettering Cancer Center in New York, found that AKT is still able to send out survival signals even when targeted by drugs that interfere with the phosphorylation reaction.
However, another type of drug called MK-2206 targets AKT in a different way, and was able to prevent the survival signals from being sent out – sending cancer cells to their deaths.
The findings, published in the journal eLife, highlight a new role for AKT in cancer, and could help scientists target the disease in ways that may have otherwise been overlooked.
AKT is part of the PI3-Kinase signalling pathway, which goes awry in the majority of human cancers, including breast and lung cancer. It fuels the disease by promoting cancer cell growth, metabolism and survival.
Several drugs have been developed to inhibit AKT – some of which work exclusively by preventing AKT acting as a catalyst for phosphorylation, while others change AKT’s 3D shape, which also blocks its association with other molecules in cancer cells. Until now, it’s not been clear which treatment is more effective.
The authors of the study treated lung and breast cancer cells with PI3K mutations using both types of AKT inhibitors to compare their activity.
They found that MK-2206, an AKT inhibitor which alters the protein’s shape, blocked AKT activity in breast and lung cancer cells, and was successful at killing cancer cells.
The researchers found that MK-2206 prevented AKT from reaching the cell membrane, which the authors believe is critical to activating the AKT functions other than phosphorylation that are necessary for keeping cancer cells alive.
But other AKT inhibitors had the opposite effect, increasing phosphorylation at the surface of cells and switching on signals that tell cancer cells to survive.
The findings identify a new type of signalling for the PI3K pathway that could help cancer cells evade treatment, but which could be targeted by new drugs.
Study co-author Dr Igor Vivanco, Leader of the Molecular Addictions Team at The Institute of Cancer Research, London, said: “The PI3K signalling pathway, of which the protein AKT plays a key role, is one of the most widely studied and most commonly deregulated pathways in human cancer. Our findings shed new light on its role in cancer and provide new evidence of a novel set of AKT-dependent signals that promote cell survival independently of previously reported activity.
“This study shows that some treatments targeting PI3K mutations in cancer cells could prevent one type of signalling mechanism driving cancer, only to have collateral damage on other processes that are just as harmful.
“Given our new understanding of how AKT functions, we need to rethink how we design drugs against it in a way that prevents these newly discovered signals, to maximise therapeutic benefit for patients.”