One of the key advantages bacteria have (versus our strategies to outwit them) is their fast turnover. Bacterial generations come along so quickly that advantageous mutations can spread through a population much faster than we can deal with the changes. And it gets worse: there are many bacterial species that actually increase their mutation rates under stress. This “adaptive mutability” mechanism (increasing the error rates when copying genetic material) is under selection pressure, too, of course – too much easy mutation and you’re bound to run into trouble – but having it in reserve has apparently been a winning strategy for bacterial species in competitive environments.
Now comes evidence that cancer cells can take advantage of the same trick. This new paper shows that colorectal tumor cells treated with the EGFR antibody cetuximab (Erbitux, which long-timers will remember as an Imclone product originally) downregulate expression of several genes in their DNA mismatch-repair system and at the same time up regulate genes that express error-prone DNA polymerases.The signs of DNA damage and mutation increased in a dose-responsive fashion. That combination is just what you see in bacteria – crank up the errors in one area, dial down a system that would fix the errors that accumulate in another. Now, most of the cells die under these conditions, but the persister cells show these adaptations, which again is just like the situation seen when bacteria are exposed to antibiotics. Meanwhile, cell lines that were already known to be resistant to EGFR antibody treatment did not change their mutation rates, presumably because they didn’t have to (they weren’t under stress on exposure to Erbitux).
Even more, tissue samples from patients who had shown partial response to chemotherapy showed these same patterns of expression. The high-fidelity DNA polymerases went down while the error-prone ones went up, and mismatch-repair genes went down as well. Now it’s true that some chemotherapy agents directly damage DNA or interfere with its repair, but EGFR inhibition is not one of those – all of that is downstream. The same sorts of effects were seen on siRNA knockdown of EGFR (and some other well-known targets such as BRAF), which ties things pretty firmly to the mechanism of action and not some general effect of the drug itself.
What kinds of mutations occur under these conditions? Whole-exome sequencing of the cells (both the starting population and the persisters after treatment) didn’t show much difference. But looking at microsatellite regions, which have a lot of replication errors even under normal conditions (and get a lot of DNA repair attention), showed significant changes in their length after EGFR inhibition (there’s a lot of nucleotide-repeat stuff in these areas). It would be interesting to know more about just what the survival benefits are to this.
So the parallels between tumor cells and bacteria have become even more clear. They have very similar strategies to deal with external attempts to shut down their growth, and just as with bacteria, their change in mutation rate is temporary. Once a population of cells establishes that has found a way to evade the chemotherapy agent, things settle back down. These results also highlight some thoughts that people have already had about strategies that directly target DNA repair and the like. If you’re going to try to kill tumor cells via such mechanisms, you need to to a thorough job of it, because if you just mildly interfere with these pathways you could be helping the tumor cell population to mutate its way into a resistant state. Just like trying to kill bacteria with antibiotics!