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 believed.
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 bowel cancer.
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 cancer.
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.
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 the body.
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.
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 Commission.