Melanoma’s ‘safe haven’ targeted for shut-down

13 April 2015

Melanoma cell. Credit: Dr Erik Sahai

Image: Melanoma cell. Credit: Dr Erik Sahai

Melanoma cells become drug resistant by using surrounding healthy cells to provide a 'safe haven' from treatment, according to new research from the Francis Crick Institute and the Cancer Research UK Manchester Institute.

Around half of melanomas are caused by a mutation in a gene called BRAF. Drugs called BRAF inhibitors treat these melanomas by targeting the faulty gene. But these cancers can quickly develop resistance to these targeted treatments. 

Scientists have discovered that a side effect of BRAF inhibitors is that they prompt healthy cells to form a 'safe haven' shielding melanoma cells from cancer drugs. So even if some cancer cells are destroyed, the protected cancer cells may survive - and the disease can recur in a form that is untreatable.

Carried out in cells in the laboratory, in mice and in samples from patients' tumours, the researchers showed that this 'safe haven' lets melanoma cells turn on a parallel set of cell signals that helps them survive. By adding a second experimental drug that blocks this alternative survival route by targeting a protein called FAK, the researchers discovered that resistance to BRAF inhibitors can be overcome. 

This combination of two drugs increased cell death and slowed growth in cell samples, and also stopped tumours from growing larger in mice.

Importantly, while not a cure, adding a second targeted therapy could help improve treatments by overcoming drug resistance and extending the time before the cancer returns. 

FAK inhibitors are being tested on their own in early stage cancer clinical trials, but it will be some years before it is known if combining these drugs with BRAF inhibitors could help patients.

Dr Erik Sahai of the Francis Crick Institute (currently based at Lincoln's Inn Fields) said: "Skin cancers caused by a faulty BRAF gene typically out-manoeuvre the targeted drugs used to treat them after a few months. Clearly understanding this process is an important first step in improving treatment.

"We've now mapped how melanoma cells exploit their neighbouring cells to survive in the presence of targeted drugs. It's clear that the 'safe haven' offered by the surrounding cells is triggered as a response to the same drugs that target this class of melanoma. Knowing more about this relationship means we can start to improve treatment."

Professor Richard Marais of the Cancer Research UK Manchester Institute at the University of Manchester, said: "Understanding the complex behaviour of melanoma cells is vital to improving survival. This research helps explain what's stopping the best drugs we have from working in this deadly skin cancer. This is early laboratory research and the next stage is to see if adding a second drug is safe and effective in patients. That said, we're making progress, and as our questions are answered we'll be able to develop and improve cancer treatments."

The paper, Intravital Imaging Reveals How BRAF Inhibition Generates Drug-Tolerant Microenvironments with High Integrin b1/FAK Signaling, is published in Cancer Cell. 

  • Melanoma cells can use surrounding healthy cells to provide a shield that enables them to resist treatment, according to new research.
  • It's hoped that understanding drug resistance of this rapidly-increasing type of cancer will help researchers find better ways to treat the disease.
  • Around 13,300 cases of malignant melanoma were diagnosed in 2011 in the UK. Over the last 30 years, rates of malignant melanoma have risen faster than any of the current top ten cancers.

Melanoma cell. Credit: Dr Erik Sahai