
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.09.03.611032
preprint
1
Article
A novel combination therapy for ER+ breast cancer suppresses drug resistance via an evolutionary double-bind
Emond Rena
West Jeffrey
Grolmusz Vince
Cosgrove Patrick
Nath Aritro
Anderson Alexander R.A. http://orcid.org/0000-0002-2536-4383

Bild Andrea H.
06 9 2024
2024.09.03.611032https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.09.03.611032
nihpp-2024.09.03.611032.pdf
Abstract

Chemotherapy remains a commonly used and important treatment option for metastatic breast cancer. A majority of ER+ metastatic breast cancer patients ultimately develop resistance to chemotherapy, resulting in disease progression. We hypothesized that an “evolutionary double-bind”, where treatment with one drug improves the response to a different agent, would improve the effectiveness and durability of responses to chemotherapy. This approach exploits vulnerabilities in acquired resistance mechanisms. Evolutionary models can be used in refractory cancer to identify alternative treatment strategies that capitalize on acquired vulnerabilities and resistance traits for improved outcomes. To develop and test these models, ER+ breast cancer cell lineages sensitive and resistant to chemotherapy are grown in spheroids with varied initial population frequencies to measure cross-sensitivity and efficacy of chemotherapy and add-on treatments such as disulfiram combination treatment. Different treatment schedules then assessed the best strategy for reducing the selection of resistant populations. We developed and parameterized a game-theoretic mathematical model from this in vitro experimental data, and used it to predict the existence of a double-bind where selection for resistance to chemotherapy induces sensitivity to disulfiram. The model predicts a dose-dependent re-sensitization (a double-bind) to chemotherapy for monotherapy disulfiram.
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pmc
