The quest to unravel the side effects of cancer drugs

So-called ‘targeted’ therapies don’t always hit the mark

All drugs have side effects.

But as anyone who’s been through chemotherapy will know only too well, those caused by cancer drugs can be tremendously difficult to cope with – as yesterday’s story about tamoxifen demonstrated only too clearly.

And while this is certainly true of chemo drugs – the mainstay of cancer drug treatment for decades – it’s also true of the newer generation of ‘targeted’ therapies, which are becoming increasingly widely used in cancer treatment.

In fact, while targeted treatments are generally more precisely engineered than their forerunners, in some people they can cause some very unpleasant side effects indeed.

But since researchers generally have a good idea of how these drugs affect the cells and tissues of our bodies, they already have a head start in understanding their side effects – which is the first step to ameliorating them.

In August, our eyes were caught by some groundbreaking research looking at the underlying causes of the side-effects of a class of drugs called EGFR inhibitors.

These drugs can cause a severe acne-like bacterial rash on patients’ skin, which – in a third of patients – can mean having to reduce the dose or stop treatment altogether. And since these drugs are becoming more widely used, it’s ever more important to work out how to block these unwanted and painful reactions.

We spoke to a couple of Cancer Research UK’s experts, to find out what they made of the new findings, and whether there’s any hope for improvements in the near future.

What are EGFR inhibitors?

In the 1980s, researchers discovered that a molecule on the surface of the cells in our bodies, called epidermal growth factor receptor (EGFR), was a key player in several different types of cancer.

Under normal circumstances, EGFR acts as a miniature satellite dish, receiving signals from the cell’s environment and relaying them to its internal communications network. Ultimately, this controls how the cell behaves, whether it divides, what other proteins it makes, and so on.

But in cancer, this process can go awry. In some cancers, for example, the tumour cells can overproduce EGFR, and over-relay these signals. In others, mutations in the DNA that produces EGFR can cause it to be permanently switched on.

Either way, these discoveries led to the development of drugs that block EGFR from relaying signals to the cell’s interior – these so-called EGFR inhibitors include cetuximab and panitumumab – sometimes given to patients with bowel cancer – and gefitinib and erlotinib, often used to treat lung cancer.

And while all of these drugs are proving very helpful in controlling a patient’s cancer, the acne-like rash they can cause is a big problem – about seven out of 10 patients develop some form of skin problem while taking the drugs.

“I couldn’t believe it,” said Jim, a lung cancer patient in his 60s, who started taking erlotinib this summer and who experienced his first ever bout of acne.

“About five days after starting taking the drug, I noticed the rash on the skin. It got quite bad over the next couple of days – it was worst by my nose and around my mouth, but also affected my head, shoulders, back and chest,” he told us.

Jim’s now taking antibiotics for the rash. “I’m trying to work out how to manage it, but I’ve generally been feeling a lot better since I took the drug, so there’is no way I would want to come off it.”

Jim’s side-effects are relatively mild. However, about three out of every 10 patients who take EGFR inhibitors have to have a reduction in dose, or stop treatment altogether.

One of the researchers who played a pivotal role in understanding EGFR’s role in cancer, and how to block it, is Cancer Research UK’s Professor Julian Downward.

“The skin problems caused by EGFR inhibitors have been a big issue for some time,” he told us.

“They have a major impact, and can lead to patients needing a reduced, less effective dose – often, these are the patients in whom the drugs work most effectively.”

In initial trials, he says, this rash was thought to be “not much more than a minor annoyance”, but as they entered more and more widespread use, it was identified as a serious issue. To control the reaction, patients are given anti-inflammatory drugs and antibiotics – but in general, he says, such strategies haven’t been massively successful.

The problem is, says Downward, that no-one really understands why the rash develops. Is it, for example, an immune reaction to the drug itself? Is it caused directly by bacteria? Or is the drug switching a particular process on or off, over and above its affect on the cancer cells?

Last week, the picture became clearer. Two research groups – one from Germany, one from the US – published studies in the leading journal Science Translational Medicine that reveal for the first time the complex immune biology causing these rashes.

Complex interactions

EGFR inhibitors cause an acne-like rash

“These papers are an excellent contribution to the field,” says immunologist Professor Adrian Hayday, a colleague of Downward’s at our London Research Institute, whose own team has been studying how the immune system reacts to EGFR drugs.

Both the German and US teams took similar yet subtly different approaches to unravel the problem, developing genetically engineered mice in whom the researchers could switch off EGFR only in the animals’ skin, and then study the consequences on the molecular level.

This revealed a complex set of interactions centred on skin cells called keratinocytes which, as well as giving our skin structure and stability, coordinates its defence against bacteria.

It transpires that keratinocytes use EGFR to receive signals from their surroundings – and blocking it causes them to malfunction, summoning all sorts of other immune cells into the skin – notably cells called macrophages – which in turn secrete chemicals that can alter many of our antibacterial defences.

“These studies show that switching off EGFR in the skin seems to profoundly mess up its normal barrier function,” says Hayday. The overall picture that the two studies paint is complex, he says, and there’s not yet a ‘smoking gun’ which might give a clue as to how to prevent the effect.

“Nevertheless, they’re extremely helpful in adding momentum to research in this arena,” he says. “We badly need these kinds of studies.

“One implication from this and our own work is that giving anti-inflammatory drugs for these side effects might not be the best strategy – instead my intuition would be to somehow bolster the immune system so  that it protects the skin’s integrity, rather than to suppress immune activities.”

As well as this, the authors of one of the papers speculate that drugs called bisphosphonates might be useful in dampening the effects, since they’re known to target macrophages.

So while these studies yield as many questions as answers, says Hayday, they establish a framework within which researchers can start to ask much more penetrating questions.

Unromantic but vital

But looking at the bigger picture, what these studies demonstrate is that cancer research isn’t just about ‘searching for cures’. It’s also about making the most of drugs we already have, understanding how they affect normal tissues, and minimising their unpleasant effects.

“It’s important stuff,” says Hayday. “Sometimes some of the guys working on skin problems are rather dismissively referred to as ‘the gels and creams brigade’, but it’s absolutely vital research – it may be slightly unromantic, but it’s serious science, with serious benefits for patients.”

Downward, too, highlights the importance of understanding how side effects occur. “Because of advances in understanding, we can now use drugs that were once virtually intolerable. A man treated for testicular cancer today will have a completely different experience of platinum-based chemotherapy than a man treated a few decades ago,” he says. This is because understanding exactly how platinum drugs affect the gut has led to the use of serotonin blockers like ondansetron, which specifically blocks this effect.

And switching back to newer treatments, researchers recently discovered why targeted melanoma drug vemurafenib caused patients to develop secondary, less serious forms of skin cancer, paving the way for combination trials to block this effect.

The EGFR inhibitors under scrutiny in this latest research are just one of several classes of targeted therapies, with many more in the pipeline. Most serious money is on the idea that to make a real impact on cancer – they’ll need to be used in different combinations, with maybe three or more drugs per patient.

Clearly, these drugs are built on the latest scientific advances, and can have dramatic, unprecedented responses in some.

But they’re also likely to lead to complex, unexpected side effects too – especially when used in combination.

So we should be thankful that researchers all over the world are already hard at work unpicking the molecular basis of how our cells work, and how these drugs affect them, so that we can continue to make sure that they’re are as effective, safe, and kind as we can make them.

Henry

Reference

• Lichtenberger B.M., Gerber P.A., Holcmann M., Buhren B.A., Amberg N., Smolle V., Schrumpf H., Boelke E., Ansari P. & Mackenzie C. & (2013). Epidermal EGFR Controls Cutaneous Host Defense and Prevents Inflammation, Science Translational Medicine, 5 (199) 199ra111-199ra111. DOI: 10.1126/scitranslmed.3005886
• Mascia F., Lam G., Keith C., Garber C., Steinberg S.M., Kohn E. & Yuspa S.H. (2013). Genetic Ablation of Epidermal EGFR Reveals the Dynamic Origin of Adverse Effects of Anti-EGFR Therapy, Science Translational Medicine, 5 (199) 199ra110-199ra110. DOI: 10.1126/scitranslmed.3005773

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