Collateral effects of drug resistance evolution: explaining repeatability and directionality patterns

Drug resistance evolution is hindering the treatment of various diseases where new drug development cannot keep pace. One possible solution to this problem could be to exploit trade-offs in resistance to already existing drugs. One such trade-off is collateral sensitivity, where resistance to one drug increases susceptibility to another. Contrarily, cross-resistance means that resistance to one drug implies resistance to another. However, the evolution of these two collateral effects is not always repeatable, nor is it always independent of drug order (i.e., bidirectional). Understanding what drives repeatability and directionality would help define the clinical applicability of collateral sensitivity and avoid cross-resistance. Nevertheless, the genetic and evolutionary mechanisms causing non-repeatability and unidirectionality patterns are not yet fully understood. In this study, we aim to define which drug concentrations, population dynamics, and genetic architectures give rise to these patterns of collateral effects. We describe minimal examples of the fewest loci and conditions needed for repeatable and non-repeatable, uni- or bidirectional cross-resistance and collateral sensitivity to occur. We show that clonal interference can explain unidirectional cross-resistance and can increase repeatability, whereas a strong selection, weak mutation regime increases non-repeatability. Additionally, we show how drug concentration can change the collateral effect and/or its pattern. Overall, we show how non-repeatability and unidirectionality of collateral effects are not properties solely of a drug pair but also of the selection regime: drug dose and population dynamics. We suggest that further studies, combining mathematical modelling with measurements of mutations and full dose-response curves for drug pairs with known patterns of collateral effects, are needed to understand this problem.