Thirty percent of all cancer cases are triggered by a faulty
KRAS gene, resulting in runaway cell division. The cancers caused
by this particular mutation - such as pancreatic cancer - are
difficult to treat. At the Netherlands Cancer Institute, a team of
researchers headed by Rene Bernards have made an unexpected
discovery that may enable cancers with this mutation to be treated
with targeted drugs in the future.
The details of their research were published in the
Nature Medicine issue of 28 May 2018
Blocking the pathway
It makes no sense to erect roadblocks if the getaway car has
already left the area. The same principle applies to the drugs used
to treat cancer inside cells. When a faulty protein is triggering a
chain reaction of problems, the only way to block that signalling
pathway in the cell is to do so 'beyond' - or downstream of - the
protein in question. It makes no sense to erect barriers 'above'
the faulty protein. At least, that's what we've always
Runaway cell division
A completely unexpected discovery by Prof. René Bernards,
postdoc Sara Mainardi, and the rest of their team at the
Netherlands Cancer Institute has cast doubt on this golden rule. At
the same time, this may offer a potential treatment for a number of
cancers that are notoriously difficult to treat. These include
pancreatic cancer, non-small-cell lung cancer, and various types of
These cancers are often triggered by a mutation in the KRAS
gene, which plays a key part in regulating cell division. Thirty
percent of all tumours are caused by this mutation. KRAS gene
mutations have been implicated in almost all cases of pancreatic
In the cell, these KRAS mutations cause the RAS protein to
become hyperactive. This generates 'fake' signals that tell the
cell to start dividing. The result is runaway cell division.
Unfortunately, there are hardly any drugs that effectively inhibit
the RAS protein itself.
So researchers previously tried to block the pathway at a point
'beyond' the faulty RAS protein, to see if that would be effective.
Unfortunately, that was not the case, as Prof. Bernards' research
group showed in 2014. This is because, once you have shut the
pathway down, feedback loops simply reactivate it again.
A failed experiment? Or perhaps not?
In a recent experiment on cells grown in culture flasks, René
Bernards tried blocking a protein 'above' RAS in the pathway. His
initial results seemed to show nothing out of the ordinary, the
blockade had no effect whatsoever, pretty much as everyone had
expected. However, when he performed the same experiment on
mice with non-small-cell lung cancer, Prof. Bernards saw something
odd. Quite unexpectedly, the blockade worked.
So this was a failed experiment. Or perhaps not? The reason for
this difference between cell cultures and living mice turned out to
be as simple as it was surprising. The cultured cells in the lab
were nourished by a serum that contains numerous growth factors.
These growth factors enable cancer cells to divide properly outside
But life in a culture flask is very artificial. Mice that have
reached adulthood have very few growth factors in their blood. René
Bernards explain that: 'Without that overkill in terms of growth
factors, the drug did indeed have an effect.' He immediately tested
this theory in the lab, by reducing the amount of serum in the
culture flasks. And - hey presto - he found that the drug worked in
cultured cells as well. 'So the old adage "in vitro we trust"
doesn't always apply', says Prof. Bernards.
RAS protein does not operate independently after all
But, more fundamentally, why does blocking the pathway 'above'
the faulty RAS protein work after all? 'In general terms, it
amounts to this - the faulty RAS protein does not operate entirely
independently', states René Bernards. The protein is, indeed,
influenced by factors from 'above'. So, in this case,
upstream interventions do, in fact, make sense.
Prof. Bernards and his regular clinical collaborator, the
internist-oncologist Jan Schellens, are now planning a clinical
trial in patients with pancreatic cancer. It will take at least
eighteen months for the trial to get up and running, as that
requires money and cooperation with the pharmaceutical company that
makes the drug in question. This will be a proof-of-concept, early
clinical trial. It will attempt to find out whether the concept
actually works in patients with pancreatic cancer, and whether the
side effects are acceptable. But even if the study produces
promising results, it will take time to develop a workable therapy.
That will require even more clinical research.
In the project described here, René Bernards was doing research
into lung cancer. The same issue of Nature Medicine contains an
article by a German researcher who has shown that the effect also
occurs in pancreatic cancer. 'That makes our result even more
robust', says Prof. Bernards.
SHP2 is required for growth of KRAS-mutant non-small-cell lung
cancer in vivo', Sara Mainardi, Antonio
Mulero-Sánchez, Anirudh Prahallad, Giovanni Germano, Astrid Bosma,
Paul Krimpenfort, Cor Lieftink, Jeffrey D. Steinberg, Niels de Wit,
Samuel Gonçalves-Ribeiro, Ernest Nadal, Alberto Bardelli, Alberto
Villanueva, and Rene Bernards.
Nature Medicine 28 May 2018
This study's sources of funding include the Center for Cancer
Genomics, the Dutch Cancer Society, EMBO and the European