Turning Evolution on Its Head

Evolution is a push and pull of selective pressures that leads to certain traits being chosen over others. Usually these selective pressures tend to be natural; sometimes, though, they can also be induced by our choices. When we spoke about tumour heterogeneity, we discussed how evolution at a molecular level can lead to the development of resistance mutations against targeted therapies. However, funnily enough, the opposite is also true. Targeted therapies can act as the selective pressure driving the evolution of cancer causing variants, leading to the frequencies of those variants increasing over time! Our efforts can indeed lead to a change in frequencies of cancer causing variants.

The first generation therapies for NSCLC (erlotinib and gefitinib) were created to target variants in exon 19 and 21 of EGFR, such as L858R. Currently, over a third of NSCLC cases are caused by an L858R variant. However, treatment with these first generation therapies has led to the development of resistance mutations such as T790M and, slowly, we are seeing an increase in the percentage of patients displaying that mutation. With the advent of Osimertinib, which is immune to T790M resistance mutations, there is an increase in frequency of new resistance mutations, such as the C797S variant, for which, in turn, new therapies may need to be explored.

It’s strange to think that, were it not for therapies developed in the last few decades, certain types of resistance mutations — — and hence certain subtypes of cancer — — may not exist. Evolution doesn’t care if the selection pressures are man-made, however. All cells “want” to live. This includes healthy cells as well as all the myriad subtypes of cancer cells, The prevalence of resistance mutations is one more example of just how tricky it is to beat cancer. Each of the Hydra’s heads needs its own, billion dollar sword.