A curative combination cancer therapy achieves high fractional cell killing through low cross-resistance and drug additivity.

Curative cancer therapies are uncommon and nearly always involve multi-drug combinations developed by experimentation in humans; unfortunately, the mechanistic basis for the success of such combinations has rarely been investigated in detail, obscuring lessons learned. 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 not synergistic interaction: together they achieve a greater fractional kill according to the null hypothesis for both the Loewe dose-additivity model and the Bliss effect-independence model. These data provide direct evidence for the 50 year old hypothesis that a curative cancer therapy can be constructed on the basis of independently effective drugs having non-overlapping mechanisms of resistance, without synergistic interaction, which has immediate significance for the design of new drug combinations.
Competing Interests: AP, CC No competing interests declared, PS is a member of the SAB or Board of Directors of Merrimack Pharmaceuticals, Glencoe Software, Applied Biomath and RareCyte Inc and has equity in these companies. In the last five years the Sorger lab has received research funding from Novartis and Merck. PKS declares that none of these relationships are directly or indirectly related to the content of this manuscript
(© 2019, Palmer et al.)