Mutations in the KRAS gene are a feature of some particularly hard-to-treat cancers, which has made it a target for many research programs over the years. The protein it codes for is way down deep in a lot of very important signaling pathways for cell growth and metabolism – growth factor signaling, glucose transport, activity of key kinase enzymes, and so on. The problem is, the KRAS protein itself has proven pretty much undruggable, as are (frustratingly) several others in that strong-oncology-story category. That’s led, naturally enough, to a number of searches for indirect approaches. These are tricky, though: the ones that are indirect enough to be workable may also be indirect enough not to hit the real target enough (or to be more efficient at affecting other things you didn’t want to touch). We actually end up finding out a lot about biochemical pathways in such projects, in the “Gosh, who knew that that was hooked up to that” sense.
For KRAS, one of these has been the attempt to inhibit the cellular process called autophagy. That’s a sort of recycling system, breaking down various cellular components in an orderly fashion while the cell itself is still very much carrying on. There are several different variations on the process, but it’s often a survival mechanism (for example, under starvation conditions), and it’s used by many cancer cells as yet another means to keep them going at all costs. KRAS mutations have been reported (by many research groups) as having a particular connection to the process of macroautophagy in particular, so its inhibition has been considered a good target.
But perhaps not any more. A joint effort from Novartis and Pfizer has resulted in this recent paper in PNAS, and it aims to break that connection. They were able to take several KRAS-mutant cancer cell lines, delete an enzyme (ATG7) that is widely accepted as being completely essential to macroautophagy, and watch as they carried on unaffected. They grew just as fiercely as before, didn’t seem to be particularly sensitized to radiation or several other chemical agents, and in general behaved as if having their autophagy mechanism shut down was a matter of no consequence at all.
Another interesting (and to many research groups, disturbing) part of the paper was a look at the old antimalarial compound chloroquine. It’s been accepted for some years now as an inhibitor of autophagy, both in vitro and in the clinic, where it’s used along with several chemotherapy regimes. There have been reports that it may not be as connected to that pathway as has been thought, but most of the references to it in the oncology literature have been of the “. . .use of the well-known autophagy modifier chloroquine has shown. . .” variety.
Well, guess what: when the autophagy pathway is taken out of commission in cancer cells by deleting ATG7, chloroquine still works, sensitizing cells to kinase inhibitors in the way that was thought to depend on shutting down autophagy. So the clinical use of chloroquine and its derivatives is certainly still valid, although now we’re not really sure why. Let the target hunts commence!
So how did Pfizer and Novartis end up publishing this paper? According to a press release by Novartis, it started with “a chance encounter at a conference”, the Keystone autophagy meeting in 2014. Both groups were presenting on their accumulated evidence that there was something wrong with the whole KRAS-autophagy story, and put together, they had a convincing case against something that had become a widely accepted fact. They’ve done the whole field a service by getting it all out there in one package.
A final philosophical point: so, what part of NIH-funded research did the rapacious drug companies rip off for this discovery? That’s a facetious question, of course, but a non-facetious one might be to try to figure out if this comes under the heading of “basic” research or “applied”. The lines between those two can get pretty blurry. Novartis and Pfizer were both trying to come up with cancer therapies, drugs to take to the clinic and eventually sell for money, and that sounds pretty applied. But to get there, cellular pathways had to be untangled and questioned, and that sounds like nothing else than basic research. I think that there are certainly cases where the two can be distinguished, but we should also realize that there are cases where they may not be. I’d rather not have the definition of basic research be “stuff that no one’s ever been able to think of a use for”.
Update: AstraZeneca has now published with more on the story.