New line of attack against cancer

In an important step towards personalised medicine, the findings from the Breakthrough Breast Cancer Research Centre at The Institute of Cancer Research (ICR) shed light on why cancer patients can fail to respond to some chemotherapy drugs and reveal a new way of targeting resistant tumours.

Until recently, it was thought cells could only die through a process called apoptosis. Because apoptosis is often blocked in cancer cells, drugs frequently don’t work, allowing tumour cells to grow and spread. In work published today online in the Molecular Cell journal, the team found some chemotherapeutics actually worked through a newly-discovered form of cell death, known as necroptosis.

Importantly, they found in the laboratory it was possible to activate a set of proteins and push cancer cells into this form of cell death, raising hope of new targeted treatments that could also kill apoptosis-resistant tumour cells.

Study author Professor Pascal Meier, from the Breakthrough Breast Cancer Research Centre at the ICR in London, said: “These findings represent a new line of attack in the fight against cancer.

"Chemotherapy has been around for decades but we have never understood how it kills cancer cells. This work shows not only that it can happen by two different processes, but how drugs can be developed to activate this newly discovered second cell-killing process in a much smarter, more effective way.

"We are at an early stage with this work but it could represent a new way of thinking about how we treat cancer patients in the future.”

The team was trying to find out how a class of chemotherapy drugs called topoisomerase inhibitors kill cancer cells. They identified for the first time how a number of key proteins involved in this process work together to kill cancer cells, finding  that the chemotherapy drugs used necroptosis instead of apoptosis.

They discovered that the complex, or set, of proteins, could be switched on to effectively kill cancer cells. Because this cell-killing action is much more prominent in cancer than normal cells, it means these proteins could make an excellent target for new, more effective, targeted treatments, with fewer side effects for patients.
It also means that patients whose tumours lack any of these proteins should not be treated with certain chemotherapeutic drugs.

Excitingly, a drug which targets one of the proteins in this complex, called SMAC-mimetics, is already showing promise in clinical trials. These results add further weight to the argument that SMAC-mimetics could be an effective cancer treatment for some patients.

Dr Julia Wilson, Head of Research Management at Breakthrough Breast Cancer, said: “This work is a major advance in our understanding of how cancer cells work, and how we can combat the disease. It suggests we can use chemotherapy more intelligently, and develop treatments which more precisely exploit this newfound weakness for the benefit of patients. We want to make sure that all breast cancer patients get the right treatment for them and this is a step towards that goal.”