Essential Role for Oncogenic Ras in Tumour Maintenance

Chin, L. et al. (1999). Nature 400: 468-472.

Now, this is a really cool paper.  Here, the authors developed mice that have a disruption in the locus that encodes two tumor suppressor genes (so these proteins are not functional) and inducibly express a particular oncogene.  This oncogene is called Ras and is one of the most common in cancer.  Ras acts as a molecular switch.  When it is on, it tells the cells to grow.  Certain mutations in Ras make it oncogenic, that is, it is always switched on (and therefore is always telling the cells to grow).  Therefore, I will refer to this mutated Ras as oncogenic Ras in this summary.

So anyway, these mice express oncogenic Ras in an inducible manner.  When you give a particular drug to them (in their water), oncogenic Ras is expressed.  When you take the drug away (and just give them normal water), oncogenic Ras is not expressed.  Pretty cool, eh?  This should turn out to be a great system to study cancer in animal models!

Now, since you need to inactivate tumor suppressor genes (that normally suppress tumor formation by inhibiting cell growth) and you need to activate oncogenes to make a cell cancerous, these mice should develop tumors when you give them the drug, right?  And they do!  Now, this was expected, but what the authors really wanted to know was whether once tumors are formed, do you still need the expression of oncogenes? 

So, first they gave the mice the drug to induce oncogenic Ras and tumor formation.  Then, after tumors were formed, they removed the drug from the water.  What do you think happened?  That's right!  The tumors regressed to barely detectable lesions!  So, not only is Ras necessary in tumor formation, but also in tumor maintenance.

What does this suggest about Ras as a target for cancer drugs?  I think it suggests that it's a pretty good target!  Not only will you prevent the formation of new tumors, but you will also cause preformed tumors to regress.  Now, although Ras is not mutated in all cancers, it is common in many of them.  So while inhibiting Ras might be effective for some tumors, it may not have any effects on other tumors. 

In the mouse model used in this paper, it was pretty easy to inhibit Ras...just withdraw the drug from the drinking water.  How do we inhibit oncogenic Ras in humans?  Well, many pharmaceutical companies are working on just that.  One class of "anti-Ras" drugs have received a lot of attention in the field recently, called farnesyltransferase inhibitors (FTIs).  Now, you're thinking..."What was that word???"  Yes, it looks intimidating, but let me try to explain.  Ras is normally anchored to the membrane of the cell by the help of a little modification called farnesylation.  Basically, this means that a farnesyl group (a fatty acid group) is added to Ras after the protein has been made.  By adding this group, Ras is now targeted and tethered to the membrane of the cell.  Importantly, Ras needs to be located here to be functional.  What is the enzyme that adds the farnesyl group to Ras?  Farnesyltransferase!  So, FTIs work by inhibiting this enzyme, and thus inhibit the localization of Ras (or oncogenic Ras) in the cell.  So far, it looks pretty promising, so we'll see will be coming out soon. 

Oh, by the way, there's some controversy on how FTIs inhibit tumor formation (and cause tumor regression).  As mentioned above, it is thought that they inhibit Ras function (by inhibiting its localization).  However, others have evidence that FTIs also interfere with other farnesylated proteins (Ras isn't the only one!), and this has important effects on the tumor.  In either case, FTIs seem to work well in mice, and hopefully humans too!

Alright, I hope you enjoyed this summary...and please check back again soon!  Thanks!