Measuring higher-order drug interactions: A review of recent approaches

Using drugs in combination can be important in therapeutic strategies, both to decrease the risk of toxic side effects as well as to decrease the likelihood of resistance evolving. These properties are largely affected by interactions among drugs. Given the increased use of three or more drugs in clinics, we provide a review of challenges researchers face when studying higher-order drug interactions together with a review of current theoretical and methodological advances in resolving these issues. The challenges include deriving theoretical measures for interaction effects compared with single drug efficacies, disentangling higher-order emergent effects from lower-order interactions, enhancing the resolution of data to better classify interaction types, and considering practical difficulties such as measuring responses to drug combinations across a range of concentrations. The systems biology and interaction modeling approaches reviewed here offer ways to go beyond-pairwise interactions and to quantify and better understand higher-order drug interactions. However, there are many research directions yet to pursue to provide mechanistic insights and to determine the consequences of these interactions.