Science Snaps: exposing melanoma’s ‘safe haven’ to help tackle drug resistance

Drug resistance is a big problem, particularly for advanced melanoma.

People with melanoma respond well to a new generation of targeted cancer drugs. And landmark research from our scientists paved the way for one of these drugs, called vemurafenib (Zelboraf).

But the sad truth has been that in many cases, the cancer cells will eventually stop responding to these drugs and the disease will come back.

Understanding the ways in which melanoma cells develop this resistance is a big challenge. But researchers from across the globe are piecing together this complex picture, uncovering an array of cellular escape routes and proposing ways to block them.

Now, Dr Erik Sahai, and his team funded by us at the Francis Crick Institute, has uncovered a new route to resistance.

Publishing their findings in the journal Cancer Cell, the researchers – working with Professor Richard Marais’ team at the Cancer Research UK Manchester Institute – shed light on how the environment around a melanoma cell may play a role in drug resistance and, crucially, offer a potential new way to stop it.

A place to hide

The image above shows brightly-coloured melanoma cells nestled among a wiry cobweb of white fibres.

These fibres are made of collagen – an important protein that forms part of the environment around a cell, called the extracellular matrix.

But just as a cobweb provides a safe home for a spider, the new study shows how the extracellular matrix may provide a ‘safe haven’ for melanoma cells and encourage resistance to treatment.

Watch an animation showing how BRAF-targeting drugs work

The melanoma cells have been engineered to produce a fluorescent sensor that tells the researchers whether a key set of signals that help the cells grow are switched on or off.

“Warm, red colours indicate high levels of signal activity,” lead researcher, Dr Eishu Hirata, tells us. “Colder, blue colours show lower levels of activity,” he adds.

These cells have been treated with a drug that targets melanoma cells carrying a fault in the BRAF gene that causes them to survive and grow uncontrollably. BRAF switches on a series of important growth signals called the ERK pathway. “If the drug is effective, the colour turns into blue, but many cells in this image retain red colours, indicating that the cells are not affected by the therapy,” Hirata adds.

So how does a drug treatment that’s initially successful in killing cancer cells slowly become something that cancer cells can tolerate?

A deadly support network

Working with experimental laboratory models of melanoma the researchers found that drug resistance only appeared when the cancer cells were grown within the extracellular matrix and among other supporting structural cells.

These specialised support cells – called melanoma associated fibroblasts – responded to the drug treatment by twisting and shaping the extracellular matrix and laying down new protein fibres at the same time.

The team found that this refreshed network acts as a ‘safe haven’ for the cancer cells, switching on a different set of signals inside the cells that reactivates the ERK pathway – and allows the cancer cells to grow again.

Switching the cell signals back on via this alternative escape route means the cells can withstand the treatment, glowing orange and red again instead of the cooler blue colours.

The next step was to find a way to halt the resistance.

The right combination

Following a meticulous set of experiments the team found that the escape signal was controlled by another important protein called FAK – we’ve written about FAK before.

The researchers reasoned that if they could switch off the FAK escape signal at the same time as the BRAF signal, then the cancer cells would be unable to become resistant to the treatment.

Crucially, drugs that target FAK are already being developed as potential cancer treatments on their own. These drugs are still in the early stages of development, but when the researchers combined an experimental FAK drug with the BRAF treatment the cancers cells stopped growing and started to die.

This was a striking result, and offers important early evidence that combining these two treatments could help control the growth of a melanoma for longer than just using the BRAF treatment alone.

From control to cure

While the combined treatments stopped the tumours from growing in the team’s lab models, the tumours didn’t go away completely – put simply, the treatment wasn’t a cure.

But the findings offer a potential window for further research to find additional treatments that could push this response from control to cure. And important studies like this one lay the ground work for what could go on to become clinical trials in people with melanoma.

It’s only by studying melanoma cells alongside the surrounding ‘supportive’ healthy cells that we’ll truly understand the best treatment approaches to test in trials.

And by peering inside this world that surrounds a tumour, Sahai, Hirata and the rest of the team are leaving melanoma cells with no safe place to hide.

Nick

• To find out more about how BRAF-targeting drugs work, watch the animation below:

Reference

• Hirata, E. (2015). Intravital Imaging Reveals How BRAF Inhibition Generates Drug-Tolerant Microenvironments with High Integrin β1/FAK Signaling Cancer Cell, 27 (4), 574-588: 10.1016/j.ccell.2015.03.008

Image

Featured image courtesy of Dr Erik Sahai, Francis Crick Institute