Almost immediately after Pfizer and Novartis provided evidence that chloroquine (used in several chemotherapy regimes) doesn’t do what people thought, another drug company (AstraZeneca, along with coworkers at Dundee) is out with a paper suggesting what it might be doing instead. The answer, if it’s the answer, is not an obvious one: it seems to be interfering with cholesterol biosynthesis. Chloroquine’s effects on bladder cancer cell lines, it turns out, can be shut down by providing the cells with extra cholesterol, and those effects can be recapitulated by giving them statin drugs or disrupting their cholesterol synthesis pathways by RNA interference.
The mechanism seems to involve lysosomal cell death, which until recently has been a little-appreciated process. (That link takes you to a full-text review which will get you up to speed, should you desire). It’s been tricky to study, because most cell death processes eventually involve the lysosomes (and their membranes), so the fact that they have a pathway all to themselves has not always been obvious. And even with the renewed attention, the exact mechanisms are not well worked out. This latest paper might provide some clues, as well as pointing out some ways to take advantage of this process in cancer therapy. The mechanism here would seem to be the cholesterol needed in lysosomal membranes to keep them from becoming too permeable.
One specific finding of this paper is that tumors with FGFR3 mutations look as if they would respond well to cholesterol pathway disruption (via chloroquine or what have you) and mTOR inhibitors. A broader implication is that cholesterol biosynthesis itself may prove to be important in a whole range of chemotherapy regimes – and this should not be a particularly difficult idea to check in the clinic. This work should give both cell biologists and clinicians some interesting experiments to set up, with results that I look forward to. And I’ll be very happy to add this one to the list of examples the next time someone tells me about how pharma does no research of its own, etc. and very much etc.