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.
The scientists’ study is rooted in basic research but has the potential to be developed into a useful clinical tool to guide lung cancer patients’ treatment. This is an abridged version of a blog by Dr Emma Smith, from Cancer Research UK, on the scientists behind this research:
Meet the good guys
Although their names aren’t quite as well-known as Batman and Robin, Fennell and Bayliss are the stars of this story.
Professor Dean Fennell is a CRUK funded clinician scientist at Leicester University. He specialises in treating people with lung cancer and leads several important clinical trials.
He’s teamed up with Dr Richard Bayliss, a structural biologist, who’s working out the shapes of proteins – the building blocks of cells.
They first started talking about how they could work together on this project after listening to a guest lecture about lung cancer at the university. We asked them to explain how their combined research efforts could have a direct impact on patients and potentially influence the treatment they receive.
The challenge – a doctor’s perspective
Lung cancer kills around 35,000 people in the UK alone and over 1.3 million people a year globally. “Because lung cancer is such an incredibly common disease it’s a massive health burden”, said Fennell.
“Since most patients will be diagnosed with lung cancer when it’s already at an advanced stage surgery is usually not an option, and drugs form the backbone of how we treat people.
“For many years standard care has been chemotherapy, but treatments targeted specifically against the lung cancer cells have been limited. But that is changing and this is where our research comes in.”
On average only about a quarter of lung cancer patients who receive chemotherapy will respond.
But for them chemotherapy is beneficial and they survive their disease longer. “What we still don’t know is how to predict who is going to respond” said Fennell. “It’s not until we do a scan afterwards that we can see whether the chemotherapy has been effective or not.”
“If we could identify subtypes of lung cancer before treatment, there are drugs already in existence we could deploy with a very high probability of the patient having a good response,” he says.
One of the drugs Fennell’s team is interested in is crizotinib, a tyrosine kinase inhibitor, which targets EML4-ALK lung cancers (ALK lung cancers for short).
“What defines ALK lung cancers is a particular fault in their DNA – two different genes (EML4 and ALK) fuse together. And this gene fusion forms a souped-up version of the protein which becomes an engine driving the cancer, and it drives it very aggressively,” Fennell explains.
“So these ALK lung cancers tend to grow very fast and spread rapidly. But the important point about this type of lung cancer is that it’s wholly dependent on this engine – and if we can somehow block this protein, the cancer can’t survive”.
And that is how crizotinib works.
This drug was shown to shrink lung cancers in patients much more effectively than chemotherapy. And that’s good news; when patients receive this treatment, most do very well indeed. But they eventually develop resistance to the treatment and the cancer starts growing again.
The key to understanding how cancers develop resistance to crizotinib, and ultimately developing more effective treatments for lung cancer, lies in figuring out what’s going on at a molecular level.
And it turns out that ALK is only half the story. And that’s where structural biologists like Dr Richard Bayliss come in.
His work involves understanding the 3-dimensional structure of the molecules inside cancer cells, such as crizotinib’s target: EML4-ALK. This is essential for designing newer ‘targeted’ drugs.
“Crizotinib blocks the ‘ALK’ part of the cancer-causing faulty protein and has been extensively studied by scientists. But virtually nothing was known about the ‘EML4’ part of the protein,” explains Bayliss. “In particular we didn’t know the shape of the EML4 protein.”
His team specialises in finding out the shapes of proteins using X-ray crystallography.
Using this technology, Dr Mark Richards (a researcher in the Bayliss lab) uncovered the structure of the closely-related EML1 protein. And because the EML1 and EML4 proteins are very similar, they were able to use this information to give a clear picture of the shape of EML4.
“When we looked at the shape of EML4 closely, it was striking that we could predict the protein’s shape would be severely disrupted by being fused with ALK, and that the protein would be quite unstable. This is fairly rare among these kinds of fusions that drive cancers,” says Bayliss.
This unexpected discovery points towards a potential target for new drugs to treat ALK lung cancers, and might help overcome resistance to crizotinib. The unstable nature of the EML4-ALK fusion means blocking a ‘chaperone’ protein, called Hsp90, is a potential new avenue.
The four-part structure of EML1 – coloured blue, green, orange and pink, these four parts come together to make the protein.
Proteins are the workhorses of our cells, carrying out all kinds of jobs from supporting a cell’s structure to creating energy, sending messages and repairing damaged DNA.
Proteins need to have a certain shape to function correctly. Chaperone proteins like Hsp90 help to fold proteins into the right shape and keep them stable – a role that becomes critical if the proteins have any kind of mistakes in them.
But cancer cells often make faulty proteins, so stopping the chaperones from working prevents the faulty proteins being folded and working properly and means the cells are likely to die.
Drugs that exploit this dependence on Hsp90 are known as Hsp90 inhibitors. But normally, neither the EML4 nor ALK proteins need Hsp90 to fold into shape correctly. But the faulty EML4-ALK fusion protein found in cancer cells is unstable, so becomes dependent on Hsp90 to help it assemble.
This is a new property that’s only found in the cancer – but not healthy – cells. “And this makes it a weakness that can be exploited by using Hsp90 inhibitors,” explains Bayliss.
The second exciting thing that Dr Bayliss and his team noticed was that EML4-ALK fusions come in several different variants, so not all patients have exactly the same faulty protein.
The ALK part is almost always the same, but the EML4 half of the faulty protein varies a lot. The two most common forms of the faulty protein (called variants 1 and 2) have unstable shapes that are likely to be dependent on Hsp90 to work properly.
“And this makes them good candidates for Hsp90-blocking drugs,” says Bayliss. “But there’s another version, called variant 3, that’s found in around a third of ALK lung cancer patients and doesn’t need help from Hsp90 to fold. This makes it unlikely that Hsp90 inhibitors will work for these people.”
Although the molecular structures from the Bayliss lab predicted that Hsp90 inhibitors should work for at least some ALK lung cancers, this idea needed to be tested in the lab, and then in patients. And this is where Professor Fennell and his clinical team come in.
Turning theory into reality
To prove this idea worked, Fennell’s team made some special cells in the laboratory with the different variants of EML4-ALK. “We were then able to test drugs that block Hsp90 to see whether the drug would work in each of the variants.
“And we found precisely what was predicted by Richard and his team – lung cancer cells that have variants 1 or 2 respond to the Hsp90-blocking drugs, but those with variant 3 don’t,” he said.
“So we can conclude from this that we now have a way of potentially predicating how well drugs that target Hsp90 are going to work for an individual based upon the exact way the EML4 and ALK genes have fused together.”
But they need evidence from clinical data and a partnership with a Boston-based pharmaceutical company is providing this crucial information. Professor Fennell is leading an international trial – called CHIARA – testing an Hsp90 inhibitor in patients with EML4-ALK fusions. This will tell Fennell and Bayliss if their theory is correct.
Source: CRUK – Emma Smith. Read the full blog here.