Local peaks and clinical resistance at negative cost

Last week, I expanded on Rob Noble’s warning about the different meanings of de novo resistance with a general discussion on the meaning of resistance in a biological vs clinical setting. In that post, I suggested that clinicians are much more comfortable than biologists with resistance without cost, or more radically: with negative cost. But I made no argument — especially no reductive argument that could potentially sway a biologist — about why we should entertain the clinician’s perspective. I want to provide a sketch for such an argument in this post.

In particular, I want to present a theoretical and extremely simple fitness landscape on which a hypothetical tumour might be evolving. The key feature of this landscape is a low local peak blocking the path to a higher local peak — a (partial) ultimate constraint on evolution. I will then consider two imaginary treatments on this landscape, one that I find to be more similar to a global chemotherapy and one that is meant to capture the essence of a targetted therapy. In the process, I will get to introduce the idea of therapy transformations to a landscape — something to address the tendency of people treating treatment fitness landscapes as completely unrelated to untreated fitness landscapes.

Of course, these hypothetical landscapes are chosen as toy models where we can have resistance emerge with a ‘negative’ cost. It is an empirical question to determine if any of this heuristic capture some important feature of real cancer landscapes.

But we won’t know until we start looking.