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.