<p>Chemotherapy remains a commonly used and important treatment option for metastatic breast cancer. A majority of Estrogen Receptor-positive (ER + ) metastatic breast cancer patients ultimately develop resistance to chemotherapy, resulting in disease progression. We hypothesized that an “evolutionary double-bind”, where adapting to one treatment inadvertently makes cancer cells more susceptible to another treatment, would improve the effectiveness and durability of response to chemotherapy. This approach exploits vulnerabilities in acquired resistance mechanisms. Evolutionary models can be used to identify alternative treatment strategies that capitalize on such vulnerabilities in refractory cancers, leading to improved outcomes. To develop and test these models, ER+ breast cancer cell lineages sensitive and resistant to chemotherapy were grown in spheroids with varied initial population frequencies to measure cross-sensitivity and efficacy of chemotherapy and add-on treatments, such as disulfiram. Different treatment schedules were evaluated to identify the most effective strategy for reducing the selection of resistant populations, thereby preventing their proliferation and dominance. We developed a game-theoretic mathematical model, parameterized 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 to chemotherapy for monotherapy disulfiram.</p>