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

How cancer metastasis happens: Researchers reveal a key mechanism

January 18, 2018
Cancer metastasis, the migration of cells from a primary tumor to form distant tumors in the body, can be triggered by a chronic leakage of DNA within tumor cells, according to a team led by Weill Cornell Medicine and Memorial ...

Modular gene enhancer promotes leukemia and regulates effectiveness of chemotherapy

January 18, 2018
Every day, billions of new blood cells are generated in the bone marrow. The gene Myc is known to play an important role in this process, and is also known to play a role in cancer. Scientists from the German Cancer Research ...

These foods may up your odds for colon cancer

January 18, 2018
(HealthDay)—Chowing down on red meat, white bread and sugar-laden drinks might increase your long-term risk of colon cancer, a new study suggests.

The pill lowers ovarian cancer risk, even for smokers

January 18, 2018
(HealthDay)—It's known that use of the birth control pill is tied to lower odds for ovarian cancer, but new research shows the benefit extends to smokers or women who are obese.

Researchers develop swallowable test to detect pre-cancerous Barrett's esophagus

January 17, 2018
Investigators at Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center have developed a simple, swallowable test for early detection of Barrett's esophagus that offers promise ...

Scientists zoom in to watch DNA code being read

January 17, 2018
Scientists have unveiled incredible images of how the DNA code is read and interpreted—revealing new detail about one of the fundamental processes of life.

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.