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Resistance Isn’t Quite Futile

Over the last few years, there’s been more attention paid to a problem in cancer therapy that is going to keep us all very busy: drug resistance. Everyone’s heard about this topic in reference to antibiotics, and with good reason. But the same thing happens in oncology, which makes sense. Despite a lot of major differences, in both cases we’re trying to kill off robust, fast-dividing cells that have a lot of genetic variation in them. Anything that doesn’t respond to the drug is going to have an open field in front of it.
The situation in cancer might actually turn out to be worse than in antibiotics, disturbing though that sounds. For one thing, cancer cell lines are often rather genetically unstable, which may well be how they ended up becoming cancer cell lines in the first place. So mutants are pretty easy to come by. Counterbalancing that, they don’t have a quick way of transferring genetic material to each other like bacteria do, which means that we don’t have to restrict the use of the therapies like we have to with antibiotics. Each patient is an island, fortunately.
The real difficulty is that antibiotics are typically taken for a set course of treatment – you knock the infection down enough to where the patient’s immune system can clean up the rest, and everything’s done. But cancer therapies, the kind that we’re turning out now, are likely going to be more like insulin is for diabetics – you’re going to be taking them for a long time, quite possibly for the rest of your life, which gives plenty of time for something bad to happen. It’s impossible to know whether all the cancer cells disappear, or whether they’re just lying low. So no one’s sure yet what will happen ifyou go off of the drugs, and as you can imagine, that’s data which is going to be hard to obtain.
Gleevec (imatinib) is a good example. There are all too many patients who have taken the drug for longer periods and have seen it lose its effectiveness, which must be really a wrenching experience. The kinase that the drug targets (Bcr-Abl) turns out to have a number of mutant forms that are unaffected by Gleevec, so any cells that have (or develop) these variants are free to cut loose. Interestingly, it may be the case that Bcr-Abl itself sets up conditions inside the cell that favor development of mutations, which for cancer cells could be something of a survival tool.
The only way around such problems is to make new drugs, just like in the antibiotic field. Two of the most advanced ones are AMN107 (nilotinib) and BMS354825 (dasatinib). Dasatinib had a good ASCO meeting, with an FDA committee recommending its approval, and with new data being presented comparing it head to head with Gleevec. So far, it looks like it’s superior to higher doses of Gleevec in CML patients who’ve started to show resistance, but this is all with blood markers (as opposed to real survival data, which naturally takes longer to come in). But so far, so good.
These might remain useful for longer, since their binding modes are somewhat different than Gleevec, and whole classes of mutant Bcr-Abl forms are still susceptible. But resistance will surely keep cropping up. We’re going to be a this for a long time.

16 comments on “Resistance Isn’t Quite Futile”

  1. A great analysis, as usual, Derek.
    As a grant-fed researcher I have no dog in this fight either way, but I’m honestly surprised to see the kinase inhibition working so well in the clinic. Given the sustained, high-level inhibition needed to get cells to die, I’ll be interested to see how drugs coming down the pipeline work that target survival factors like IAPs.
    One would think that even briefly knocking out survival pathways (IAPs, aerobic glycolysis) might be more effective than kinase inhibitors since tumor cells normally survive in environments where no self-respecting cell would be found. That’s without even getting into the long-awaited realization of anti-angiogenic therapies, surprisingly low impact this ASCO meeting. But, then again, I think I’m wise enough to know that there is plenty of biology known in pharma that never makes it to the stuff I read.
    Also, I think that pharma might somehow find a way to capitalize on chemoprevention, the most effective cancer “treatment” known. Statins are nicely analogous in CV disease but there’s no easy serum surrogate like cholesterol for cancer…yet.

  2. Steven Jens says:

    I would think the “each man is an island” factor would help the pharmaceutical industry in the long-run, too; just as cancer doesn’t propagate from one person to another, strains of cancer don’t evolve in the population over time. Bacteria can get more sophisticated over time, and penicillin doesn’t do much, but even if a cancer drug loses its effectiveness for a given patient, Gleevec should still be useful in a new cancer patient 50 years from now. No part of the arsenal becomes obselete (unless, I suppose, something better comes along that operates against the exact same target).
    Or do I not know what I’m talking about? I’m not always sure.

  3. DLIB says:

    Assuming simple target variation ( versus efflux…) what makes one drug more susceptible to resistance versus another. How do med chemisits optimize to prevent this? Does med chem exacerbate this?

  4. lynn says:

    The analogy with antibiotic resistance is interesting (and maybe useful), in that the search for new antibacterials has been centered for years on inhibitors of single essential genes, and has been singularly unsuccessful – in part because resistance mutations in the target can occur rapidly. Successful antibiotics used for systemic monotherapy are aimed at multiple targets. One way around this is to create a single agent with multiple targets (one pharmacophore hitting two related enzymes – or hybrid molecules with two pharmacophores hitting unrelated targets), to target a structure that is the product of multiple genes (like the cell wall, cell membrane, DNA), or to use combinations (as has been done in oncology and virology).
    To address DLIB’s question using the bacterial analogy, the observed mutation frequency of a target to resistance is generally related to the number of possible sites in the target gene at which a mutation to resistance can occur. In bacteria, if only a specific single base change can give resistance, then the frequency is on the order of 1 in 10^9 (per bacterial cell per generation); if more sites can be mutated to give resistance, the frequency is higher. Similarly, if knockout of a gene can give resistance, the frequency can be as high as 10^-6. So target choice is important – but so is the structure of the inhibitor. For example, if the inhibitor is very similar to a normal enzyme substrate, then changes which prevent inhibitor binding may also change substrate binding, leading to an inactive enzyme (not resistance); if the inhibitor makes contacts outside the minimal active site, then changes that disable the enzyme less are consistent with retention of enzyme activity – and can lead to resistance. Med chemists, crystallographers, biologists are all involved in target and inhibitor choice [says this microbiologist].

  5. Derek Lowe says:

    Abel P, we’re actually kind of surprised at how well these things work, too. It’s not that they’re just wiping out cancer – they’re not, although they’re doing some good – it’s just that everyone thought they might be too toxic.
    Steven Jens is right – the cancer agents aren’t going to find their effectiveness eroded in the way that antibiotics do. We’re not fighting a distributed network like the bacterial world, which is certainly a good thing.
    And as for DLIB’s question, for the most part we don’t know the exact forms that resistance will take until the first drugs hit the market. There are so many possibilities for protein mutations, and our ability to model them is so poor, that we usually just have to wait and see what happens, and then try to compensate for it. The more drugs, the merrier.
    I’m waiting for Angell or someone to complain about all the worthless “me-too” drugs in oncology. . .

  6. Jeremiah says:

    I disagree with the assumption that the situation is worse in cancer than antibiotics. For one, as you have pointed out, developing resistance to oncotherapeutics is only going to impact the immediate patient, given that cancer isn’t communicable. Further, updating cell lines isn’t horribly difficult. More importantly, if you look at morbidity statistics before the advent of antibiotics, actually getting old enough to develop cancer wasn’t nearly as common as today. I don’t mean to sound like an alarmist, but the rate bacterial resistance and the rate of new drug development is horribly disproportional. There was a time, not too long ago, when infection was a greater threat than cancer. (Though I have no idea how the development of sanitization in the OR has impacted that, but given every post-op has an IV drip of antibiotics I assume it isn’t enough.)

  7. jeet says:

    Don’t forget viral examples (HIV) for instance. Granted that cancer cells and bacteria have a lot more genetic material to work with, but the advances in multi-drug HIV supression may be something of a model for cancer treatment.
    I’m of the school that the biggest impact to cancer mortality is due to prevention and early detection. Prevention has really become a huge impact on the projections for lung cancer in the US. Early detection leads to early treatment – hopefully way before you go stage IV

  8. Chrispy says:

    It is a little sad how once one drug (like Gleevec) clinically validates a target that you have so many people trying all of a sudden to hit that same target. I was among those who thought Gleevec would never work (ATP-competitive, unselective kinase inhibitor? With ATP at 1mM in the cell?). Although I was happy to be proven wrong, I am a little dismayed that we are still going after kinases with ATP-competitive inhibitors. I think this class of drugs has fundamental liabilities which we’re seeing played out in Gleevec.
    By the way, who the heck is taking all the Gleevec? I thought CML was a tiny market, but Gleevec is clearly doing gangbusters business…

  9. srp says:

    Once a cancer drug is used in a population of patients, is there a typical succession pattern of mutations for resistance? If there is, then one could imagine coming up with a staged regime of drugs that switched over the course of treatment or when the first agents started to lose their effectiveness.

  10. Heatmiser says:

    I don’t know about repeated succession, but I recall a paper/article on EGFR and Tarceva. The investigators kept seeing the same mutation pop up in different patients who eventually became resistant. So, yes, for at least one round, you could be treated with Tarceva, predictably develop Mutation X and then be treated with the EGFR inhibitor that worked with Mutation X.

  11. secret milkshake says:

    desatinib looks like a good drug. I would worry about poor selectivity Src vs Lck – the later will cause imunosupression. In fact, this is one of the desatinib side-effects.
    It is clear that multi-targeted kinase cancer drugs have potentially a better efficacy than single-target drugs (you need double or tripple whamy to shut down all possible escape routes for invasion/multiplication) but it is difficult to guess what the desirable profile and even more difficult to develop such a drug that hits several targets without hitting something else (and having mechanism-based tox). Part of the problem is that many companies have tendency to put strongly basic side-chains onto their kinase inhibitors – this tends to improve the potency and solubility and increases tissue distribution and organ accumulation but it can cause non-specific tox (for example by hitting ion chanels). I would recommend to stay away from strongly basic secondary and primary amines.

  12. JohnH says:

    Chrispy, yes CML is presently a tiny market but growing. As each year more people are diagnosed and less are dying from CML due to wonderful results of Gleevec. So navaritis has itself a nice cash cow.

  13. Paul Dietz says:

    Cancer may not be communicable in humans (except perhaps between identical twins or immune deficient patients?) but it’s devastatingly communicable in tasmanian devils.

  14. Conrad says:

    Has anyone any knowledge of how VX 680 or any other drug is doing against the T315I mutation.

  15. Sandy says:

    No matter what commercials say but I still have that strong feeling that there is no way of curing cancer and all those cases of progressive treatment are pure incidents and all human beengs can do is in the world of surgery.

  16. divya says:

    i have done my microbiology and qc training

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