Searching for Drug Synergy in Complex Dose–Response Landscapes Using an Interaction Potency Model

TLDR

Rational design of multi‑targeted drug combinations is a promising strategy to tackle drug resistance, yet existing reference models—developed for low‑throughput experiments—often fail to capture the complex interaction patterns seen in large‑scale dose‑response matrices. The study proposes the ZIP reference model and an interaction‑landscape approach to better capture drug interactions across full dose‑response matrices. ZIP quantifies interaction by comparing potency shifts between single drugs and combinations, using a delta score that equals zero only under probabilistic independence and dose additivity, and the interaction‑landscape maps these deviations across the entire dose‑response matrix. In a large‑scale anticancer study, ZIP accurately identified confirmed synergies with a low false‑positive rate, and the interaction‑landscape further enhanced differentiation among drug‑combination classes, aiding mechanistic insight for clinical translation.

Abstract

Rational design of multi-targeted drug combinations is a promising strategy to tackle the drug resistance problem for many complex disorders. A drug combination is usually classified as synergistic or antagonistic, depending on the deviation of the observed combination response from the expected effect calculated based on a reference model of non-interaction. The existing reference models were proposed originally for low-throughput drug combination experiments, which make the model assumptions often incompatible with the complex drug interaction patterns across various dose pairs that are typically observed in large-scale dose-response matrix experiments. To address these limitations, we proposed a novel reference model, named zero interaction potency (ZIP), which captures the drug interaction relationships by comparing the change in the potency of the dose-response curves between individual drugs and their combinations. We utilized a delta score to quantify the deviation from the expectation of zero interaction, and proved that a delta score value of zero implies both probabilistic independence and dose additivity. Using data from a large-scale anticancer drug combination experiment, we demonstrated empirically how the ZIP scoring approach captures the experimentally confirmed drug synergy while keeping the false positive rate at a low level. Further, rather than relying on a single parameter to assess drug interaction, we proposed the use of an interaction landscape over the full dose-response matrix to identify and quantify synergistic and antagonistic dose regions. The interaction landscape offers an increased power to differentiate between various classes of drug combinations, and may therefore provide an improved means for understanding their mechanisms of action toward clinical translation.