Date Published: 24 March 2014

EML 1 protein to help medics predict which lung cancer patients will benefit from Hsp90 inhibitors

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Scientists working for Cancer Research UK have announced the discovery of the structure of an abnormal protein called the EML 1 protein, which causes an aggressive type of lung cancer.

The atomic surface of the EML1 protein is shown above/right. As shown, the structure consists of four parts which are indicated in the diagram by the colours blue, green, orange and pink.

It has been suggested that the revelation of the structure of this protein, which is understood to be formed due to a genetic fault, could enable doctors to predict who will benefit from a specific lung cancer treatment, while saving other patients from receiving it unnecessarily.

The researchers involved in this project were studying a form of lung cancer known as ALK lung cancers, which account for around 4% of lung cancer cases. These lung cancers involve a fault in which two different genes become fused together. This gene fusion forms a "souped-up version" of a protein which then acts like an engine, driving the cancer to grow quickly and spread rapidly. Critically, these particular cancers rely on this specific "engine" (mechanism) in order to survive. Therefore blocking this protein could kill the lung cancer.

Using x-ray crystallography, researchers developed a clear picture of the shape of one half of the souped-up protein. The shape of the other half was already known. This revealed several different shapes depending on where the genes had fused. Some of the shapes are unstable and need help from another protein to work. The assistant protein can be blocked by drugs known as Hsp90 inhibitors. By stopping this helper protein, the unstable, souped-up proteins can no longer work and so the cancer cells die.

However, unfortunately for around one third of patients with ALK lung cancer, the structure of the protein revealed by the researchers is much more stable and is resistant to the Hsp90 inhibitors.

Following their discovery, the researchers grew cells in the lab to test their theory. The cells with the unstable protein were killed by the drug but the cells with the stable form of the protein continued to grow. The researchers are now collecting data and samples from a clinical trial to find out if their lab findings hold true in people - not just in the lab - and so can be used to predict which lung cancer patients will respond to the drug.

Dr Richard Bayliss, co-author based at the University of Leicester and the Cancer Research UK Leicester Centre, said:

" We routinely use protein structures during the process of drug design, but this is the first time they have helped us to predict patient response to drugs in clinical development. The other unique aspect of this project has been the bringing together of teams who hadn't previously worked together. We had structural biologists working alongside clinical researchers who help treat patients. Our results would not have been possible without the clinical oncology expertise of Professor Dean Fennell and his team. We're now looking for groups of patients who might benefit from Hsp90 inhibitors because they harbour other 'souped-up' proteins with unstable shapes."

Dr Emma Smith, Cancer Research UK's senior science information officer, said:

" This study is a positive step forward in making sure lung cancer patients get the most effective treatment based on the genetic mistakes that underpin their disease. We now need to build on this research and gather further clinical data to confirm these findings. It may lead to doctors developing a simple genetic test to spot patients who will benefit from a drug targeted against their disease, and spare patients unlikely to benefit unnecessary side effects.
_ Lung cancer has been a difficult disease to overcome. Unravelling the mystery of its complex biology, and developing better and kinder treatments is taking time but this research provides yet more hope that we're moving in the right direction."

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