Drugs in a Curative Combination Therapy for Lymphoma Exhibit Low Cross-Resistance But Not Pharmacological Synergy

Almost all curative cancer therapies involve multi-drug combinations. The development of new combinations currently focuses on identifying instances of synergistic pharmacological interaction. Historically successful curative therapies were developed by experimentation in humans using different criteria but the mechanistic basis of these successful combinations has not been investigated in detail. Here we use isobologram analysis to score pharmacological interaction and clone-tracing and CRISPR screening to measure cross-resistance among the five drugs comprising R-CHOP, a combination therapy that frequently cures Diffuse Large B-Cell Lymphomas. We find that drugs in R-CHOP exhibit very low cross-resistance but no synergy; their combined activity is close to dose-additive (Loewe model) and effect-independent (Bliss model). These data provide direct evidence for the 50-year old hypothesis that a curative cancer therapy can be constructed on the basis of non-overlapping resistance among individually effective drugs, rather than pharmacological interaction.