Discovery to help predict who will benefit from lung cancer treatment

March 25, 2014, Cancer Research UK
This shows the atomic surface of the EML1 protein. The structure is made of four parts that are coloured blue, green, orange and pink. These four parts come together to make the souped up protein.

Cancer Research UK scientists have discovered the structure of an abnormal protein which causes an aggressive type of lung cancer, according to new research* published in the Proceedings of the National Academy of Science on Monday.

Unveiling the structure of this – formed by a genetic fault – could enable doctors to predict who will benefit from a specific treatment, while saving other from receiving it unnecessarily.

Researchers were looking at a form of the disease – known as ALK lung cancers – which account for around four per cent of cases.

These lung cancers have a fault where two different genes become locked together. This gene fusion forms a souped-up version of a protein which then becomes an engine, driving the cancer to grow very fast and spread rapidly.

But, importantly these cancers rely on this engine to survive so blocking the protein could kill the lung cancer.

Using x-ray crystallography, the researchers were able to develop 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.

Crucially, some of the shapes are unstable and need help from another protein to work. This 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 the cancer cells die.

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

Following on from their discovery, the researchers grew cells in the lab to test their theory. As predicted, the cells with the unstable protein were killed by the drug, and the cells with the stable form of the protein continued to grow.

The researchers are currently collecting data and samples from a clinical trial to find out if their lab findings hold true and 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 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."

Explore further: Ganetespib shows potency against ALK-positive lung cancer and overcomes crizotinib resistance

More information: Mark W. Richards, Edward W. P. Law, La'Verne P. Rennalls, Sara Busacca, Laura O'Regan, Andrew M. Fry, Dean A. Fennell, and Richard Bayliss. "Crystal structure of EML1 reveals the basis for Hsp90 dependence of oncogenic EML4-ALK by disruption of an atypical β-propeller domain." PNAS 2014 ; published ahead of print March 24, 2014, DOI: 10.1073/pnas.1322892111

Related Stories

Ganetespib shows potency against ALK-positive lung cancer and overcomes crizotinib resistance

March 26, 2013
A drug that indirectly impairs the function of several cancer-driving proteins, including anaplastic lymphoma kinase (ALK), may be an effective new treatment for patients with ALK—positive non-small cell lung cancer.

Blocking 'lock and key' site of lung cancer proteins could lead to new treatments

November 12, 2013
A Cancer Research UK study reveals that stopping two essential lung cancer proteins from joining together at their 'lock and key' site could lead to new treatments for the disease. The research is published in the journal ...

New drug extends advanced lung cancer survival

June 3, 2013
A new drug can help advanced lung cancer patients live longer and may aid in treating other kinds of cancer, researchers said Monday.

Experimental drugs for breast cancer could treat lung cancer too

August 13, 2013
Cancer Research UK -funded scientists have discovered that experimental drugs first developed for breast and ovarian cancer could be used to treat the most common type of lung cancer, reveals research published in Oncogene ...

Scientists discover new protein involved in lung cancer

February 27, 2014
Scientists from The University of Manchester – part of the Manchester Cancer Research Centre (MCRC) - have discovered a new protein that is involved in cancer and inflammation in lung tissue.

Recurrent but rare mutations might underlie cancer growth

February 26, 2014
A potential new gene mutation that might drive lung cancer development and growth has been identified by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard ...

Recommended for you

Single-cell study in a childhood brain tumor affirms the importance of context

April 20, 2018
In defining the cellular context of diffuse midline gliomas, researchers find the cells fueling their growth and suggest a potential approach to treating them: forcing their cells to be more mature.

Aggressive breast cancer already has resistant tumour cells prior to chemotherapy

April 20, 2018
Difficult to treat and aggressive "triple-negative" breast cancer is chemoresistant even before chemotherapy begins, a new study by researchers from Karolinska Institutet and the University of Texas MD Anderson Cancer Center ...

Mechanism that drives development of liver cancer brought on by non-alcoholic fatty liver disease discovered

April 19, 2018
A team of researchers from several institutions in China has found a mechanism that appears to drive the development of a type of liver cancer not caused by alcohol consumption. In their paper published in the journal Science ...

Discovery adds to evidence that some children are predisposed to develop leukemia

April 19, 2018
St. Jude Children's Research Hospital researchers have made a discovery that expands the list of genes to include when screening individuals for possible increased susceptibility to childhood leukemia. The finding is reported ...

Scientists identify 170 potential lung cancer drug targets using unique cellular library

April 19, 2018
After testing more than 200,000 chemical compounds, UT Southwestern's Simmons Cancer Center researchers have identified 170 chemicals that are potential candidates for development into drug therapies for lung cancer.

Chip-based blood test for multiple myeloma could make bone biopsies a relic of the past

April 19, 2018
The diagnosis and treatment of multiple myeloma, a cancer affecting plasma cells, traditionally forces patients to suffer through a painful bone biopsy. During that procedure, doctors insert a bone-biopsy needle through an ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.