Figure 1. Fitness landscapes and transversion upon drug treatments.

(A) An illustration of a fitness landscape in 3-D space, with the x and y plane representing genotype space and the z axis representing fitness. The white asterisk indicates a possible initial genotype of the tumor population. The fitness landscape with the corresponding peaks and valleys is one possible realization of the fitness under drug A. Upon selection with drug A, the likely evolutionary trajectory is shown in blue. Alternatively, upon selection with drug B, the population can transverse the fitness landscape with a different trajectory and terminal state (shown in red). These drug selection perturbations open opportunities for rational design of subsequent treatment strategies (e.g. I vs II). (B) In strategy I (‘evolutionary trap’)⁷⁵, drug B can be used to drive the tumor toward a specific state such that the resulting tumor genotype state will be vulnerable to another drug C. The corresponding fitness landscape under drug C is shown. (C) In strategy II (‘temporal collateral sensitivity’)⁸⁰, by understanding the propensity and trajectories of tumor evolution under the canonical drug A selection, there may exists vulnerabilities at intermediate stages of clonal evolution we can exploit. Based on the fitness landscape shown for same genotype space under drug D, we see that we can switch to drug D when the tumor is evolving (under drug A) at a particular intermediate state for maximized kill.