Rationales for Combining Therapies to Treat Cancer: Independent Action, Response Correlation, and Collateral Sensitivity Versus Synergy

The principle of independent drug action proposes that responses to drug combinations result from responses to one or the other of two combining agents, but not both. Explorations of biological pathway interactions in signal transduction and immunobiology as synergy have not been connected to mathematical demonstrations of above–independent action activity, which would define pharmacologic synergy. We review independent action as the explanation for cancer drug combinations and find no evidence for pharmacologic synergy. Rather, a measure of correlation of response ( ρ) when positive can explain below–independent action results, and negative correlation can explain above–independent action results. Anticorrelated responses may be a mathematical demonstration of collateral sensitivity, which can achieve above–independent action activity. Inappropriate use of biological concepts of synergy may be contributing to high failure rates for immuno-oncology clinical trials, indicating a need for more rigorous applications of independent action to the development of cancer drug combination therapy. Expected final online publication date for the Annual Review of Cancer Biology, Volume 7 is April 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.