Blocking the escape routes: how an HIV drug exposes skin cancer’s weaknesses

Thanks to the diligent digging of our researchers and others around the world, a ground-breaking study was published back in 2002 identifying faults in a gene called BRAF as playing a major role in skin cancer. Around half of all melanomas – the most serious type of skin cancer – are caused by faulty BRAF molecules.

The impact of this finding was huge. As well as revealing vital information about how melanomas develop, it directly led to the first targeted drug for advanced skin cancer – vemurafenib (Zelboraf) – that was approved for use on the NHS in 2012.

Watch an animation showing how targeted cancer treatments work

But there’s a problem. While drugs targeting faulty BRAF molecules can halt the disease’s growth and spread, it’s only a temporary slow-down. Melanoma nearly always finds a way to override the treatment, and start growing again.

Over several years researchers have been meticulously mapping the genetic landscape of resistant disease, hoping to figure out the escape routes skin cancer uses to evade the drug’s effects – and stop this happening.

But it’s become clear that skin cancers are highly unstable at the genetic level. Instead of discovering one or two genetic escape routes as hoped, scientists are faced with something that looks more like the London Underground map. The sheer numbers of paths skin cancer can take to become resistant makes blocking them seem an almost impossible task.

But to tackle this challenge, Professor Claudia Wellbrock, and her team at the University of Manchester, took a step back to look at what was happening much earlier in the path to resistance, and they came across something surprising. Skin cancer relies on a rescue kit.

Taking away skin cancer’s rescue kit

“There’s a year or so where skin cancer responds well to drugs targeting BRAF,” explains Wellbrock.

“We wanted to look at what was happening in the cells during this window to lead up to the development of resistance.”

And when they analysed skin cancer samples from 11 people given BRAF inhibitors they saw a rapid molecular re-wiring inside the cells. Within the first fortnight of treatment, levels of a molecule called MITF shot up. MITF is what’s known as a ‘transcription factor’ – it can stick to DNA and turn on other genes – in this case, genes which allow cells to keep growing in harsh conditions.

“MITF is an immediate ‘rescue kit’ the skin cancer cells turn on to help them survive the onslaught of treatment,” Wellbrock tells us.

But the really interesting thing, she says, was that the high levels of MITF weren’t caused by further genetic mistakes in the cells – it was just in reaction to the drugs’ effects. “This suggested to us that, in theory at least, it could be reversed.”

To find out if it could, the team set out to test 640 drugs, all of which had already been approved as medicines by the FDA (the US medical regulator).

And they found one that was particularly potent at reversing MITF’s effects – an HIV therapy called nelfinavir.

“When we treated skin cancer cells growing in the lab with a combination of nelfinavir and a BRAF drug, we saw that the cells became much more sensitive to the treatment,” says Wellbrock.

“And when we took the study one step further, we found that the combination of treatments also kept skin cancer under control in mice too.”

The team even found that nelfinavir could re-sensitise melanoma cells that had already become resistant to drugs targeting BRAF, suggesting that this MITF ‘survival kit’ could be a vital weakness.

Melanoma cells dying in the lab following treatment with both drugs (dying cells shown in red and yellow).

A new role for an HIV drug?

Scientists have been interested in the cancer-fighting properties of nelfinavir for a while, after doctors observed that people taking HIV treatment were less likely to develop and die from Kaposi Sarcoma and HIV-related non-Hodgkin lymphoma.

Our data suggest that the power in this approach lies with attacking cancer from two angles

– Professor Claudia Wellbrock, Cancer Research UK

Early clinical trials are on-going in the US, but results so far have been disappointing. “The clinical trial results so far have only been from using nelfinavir by itself,” Wellbrock tells us. “Our data suggest that the power in this approach lies with attacking cancer from two angles – hit them with the toxic drug and take away the rescue package they use to survive.”

The team only looked at samples from a relatively small number of people, so the next steps will be to look in bigger groups of patients to find out if MITF is ramped up in most skin cancers before planning possible clinical trials.

“We were so excited seeing the effectiveness of the combined treatments in mice,” says Wellbrock.

“There’s a long way to go before we can say it works in people with skin cancer, but it’s certainly looking promising so far.”

Emma