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Evading Chemotherapy, Bacteria-Style

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!

17 comments on “Evading Chemotherapy, Bacteria-Style”

  1. Project Osprey says:

    So can we now think of cancer as being a sort of cellular anarchy where we go from being multicellular organisms to microbial colonies… a bit like John Carpenter’s The Thing

    1. Derek Lowe says:

      Exactly! In fact, I’ve just added a link to this article, which shows that other people have had just that thought – albeit without the John Carpenter reference, although I think that does add something:
      https://science.sciencemag.org/content/360/6396/1391

      1. Project Osprey says:

        Kind of makes me wonder about treating it as a microbe… Immunotherapy has been so effective. Has phage therapy been tried?

        1. Barry says:

          yes, Frank McCormick’s “oncolytic ‘phage” is still worked on.

          https://www.ncbi.nlm.nih.gov/pubmed/30146692

      2. LdaQuirm says:

        Do they reference CTVT & DFTD? Seems relevant here. Not relevant however, but amusing to think about, is that phylogenetically speaking; CTVT is a breed of single celled parasitic dog. I wonder what the standards for it are with the American Dog Breeders Association.

    2. Rothbard says:

      Apoptosis is theft!

  2. Andy II says:

    Fascinating similarity between cancer cells and bacteria. Big difference is that companies working on drug-resistant cancer treatments rush to grab $$$$ while companies working on drug-resistant bacteria rush to file bankruptcy.

    1. John Wayne says:

      Both therapeutic areas are hard, but one of them is getting paid.

      1. Frankenstein says:

        capitalism is deciding what we will die of…

  3. Troy Boy says:

    “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.”

    But you also need to make sure that by targeting DNA repair, you’re not pushing normal cells into a state of hypermutation, too. Chemotherapy/DNA damaging agents are toxic to the cancer cells, but normal cells have the ability to fix the damage to their DNA.

  4. Some idiot says:

    Stupid question of the day: how do they (bacterial cells, cancer cells) do the up/down regulation required? Do all human cells do this? What is the mechanism? Could this be a path to finding something to reduce resistance?

    Or is it just natural selection (the wording of the blog indicates that it is active, not just passive)?

    1. TruthOrTruth says:

      Not a stupid question! I imagine the authors wonder the same thing. At the end of the day, changes in gene expression occur through sequence-specific transcription factors. How you go from antibody binding to its target protein to transcription factors re-wiring the expression of the cell, that’s the work of at least one NIH R01 application!

    2. Jonathan says:

      Right? It’s easier to imagine how this “mutate-to-survive” strategy evolved in bacteria. Cancer cells haven’t had millions of years of natural selection.

      This paper is outside my area, but I was wondering, could there be a different reason why the antibody causes upregulation of error-prone DNA polymerases? Is it specific to this one antibody or EGFR inhibition, or is it more general?

      1. Hap says:

        Except we came at one point from bacteria – we diverged awhile ago but there’s a lot of stuff in our genome, and maybe some of it is still there, waiting to be picked up.

        Is this amenable to an antibody/5-FU sucker punch?

  5. Barry says:

    Weinberg added “genetic instability” to his “Hallmarks of Cancer” already in 2011

    https://www.ncbi.nlm.nih.gov/pubmed/21376230

  6. Larry Hardy says:

    Fundamental similarities between bacterial and mammalian genetic approaches to increase probability of survival is really not that surprising. I’m reminded of suggestions from John Cairns and colleagues, which were controversial but had great impact, that environment can influence which types of mutations are “chosen” to predominate by an organism.
    Cf.: https://www.nature.com/articles/335142a0.pdf

  7. Sev says:

    couldn’t that be a chance? First treating cancer cells with a drug to up regulate their mutability and then hit them hard with mutagenic substances?
    they might not be able to handle the stress anymore…

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