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

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Abstract

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.

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All data generated during this study are included in the manuscript and supporting files. Source data is provided for all clone tracing and CRISPR screen experiments.

Article and author information

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Adam C Palmer

Laboratory of Systems Pharmacology, Harvard Medical School, Boston, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0001-5028-7028
Christopher Chidley

Laboratory of Systems Pharmacology, Harvard Medical School, Boston, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-8212-3148
Peter K Sorger

Laboratory of Systems Pharmacology, Harvard Medical School, Boston, United States

For correspondence
peter_sorger@hms.harvard.edu

Competing interests
Peter K Sorger, 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 Sorgerlab has received research funding from Novartis and Merck. P.K.S. declares that none of theserelationships are directly or indirectly related to the content of this manuscript.

"This ORCID iD identifies the author of this article:" 0000-0002-3364-1838

Funding

National Institutes of Health (P50-GM107618)

Adam C Palmer
Christopher Chidley
Peter K Sorger

National Institutes of Health (U54-CA225088)

Adam C Palmer
Christopher Chidley
Peter K Sorger

National Health and Medical Research Council (1072965)

Adam C Palmer

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.