How cancer escapes chemotherapy

Prof. Mel Greaves

This is a heads up for a very useful essay, written by Mel Greaves, for The Darwin Cancer Blog – a blog dedicated to commenting on evolutionary approaches to cancer. In this essay, titled “Ways of Escape”, Greaves draws a number of comparisons between chemo-resistance in cancer and antibiotic resistance in bacteria. Both, he points out, frequently come about because the therapy we throw at either bugs or cancer cells selects for pre-existing mutations, rather than inducing de novo mutations (which of course does also occur). Bacteria, he says, that have been discovered in 30,000 year-old permafrost, have mutations that render them resistant to modern antibiotics, for instance. The cancers for which chemotherapy is a success story are very few in number: testicular cancer, acute lymphoblastic leukaemia, and choriocarcinoma – they are the only ones, to date, which retain sensitivity to cancer drugs. In most other cases chemotherapy will have short-lived positive effects but, thanks to selection among cancer clones within the tumor mass, the cancer likely re-occurs with a vengeance.

Cancers are only playing the same evolutionary tricks common throughout the plant and animal kingdom. Escaping from potentially lethal challenge has been a major driving force in evolution, he says, and the majority of species on Earth are parasites and their success depends on immune evasion or disguise. The evolutionary principle could not be simpler – it’s survival of the fittest and the luckiest.

“Given that cells and micro-organisms both divide and mutate, the likelihood of the existence of a mutation endowing resistance is going to be determined by the clone size (number of cells) and the mutation rate. This is why small or ‘early’ tumours are less likely to appear to be resistant. When bacteria are subjected to high levels of stress, they adopt a mutator phenotype which greatly increases the probability of mutations favouring survival. By increasing background mutation rate, the instigation of genetic instability in cancer increases the chance of drug-resistant mutations. The prediction that escape mutations pre-date exposure to cancer drugs and that drug treatment would, essentially, positively select emergent clones with these mutations has now been validated with high depth sequencing of diagnostic samples from patients who later relapsed on targeted drug therapy. It is perhaps one of the ironies of cancer chemotherapy that intensive drug treatment provides strong selective pressure for the emergence of more robust clones.”

Greaves goes on to explain a number of Houdini acts common among cancers before asking what we can do about it. We need to be smarter, he says, which is why we are seeing some success with combinatorial therapy, employing a number of cancer toxins to cut off several escape routes at once. Alternatively, he says, we can make use of appropriate scheduling and dosage of drugs to push cells into a more benign evolutionary trajectory or lower fitness cul-de-sac. This is the “live with cancer, rather than try to eradicate it” approach taken by Bob Gatenby and his colleagues at the Moffitt Cancer Center in Florida.