Abstract 3164: Disulfiram re-sensitizes ER+ breast cancer cells resistant to chemotherapy through an evolutionary double-bind

Abstract

Abstract Most ER+ metastatic breast cancer patients develop resistance to endocrine therapy and are also typically cross-resistant to chemotherapy, resulting in disease progression. However, chemotherapy resistant lines have been shown to acquire cross-sensitivity to therapies such as disulfiram, a drug used to treat alcoholism. Because of this cross-sensitivity, we hypothesized the existence of an “evolutionary double-bind”, a situation where treatment with one drug improves the response to a different agent. This can occur when resistance mechanisms rewire key proliferative pathways, creating potentially targetable vulnerabilities to be exploited. While recent studies have applied theoretical ecological and evolutionary principles in understanding cancer progression, it remains a new and exciting endeavor to quantify effective evolutionary games in refractory cancer to design alternative treatment strategies that induce an evolutionary double-bind. Here, we developed ER+ breast cancer cell lines sensitive and resistant to paclitaxel or doxorubicin to test the cross-sensitivity and efficacy of chemotherapy and disulfiram as an alternative treatment strategy. To quantify this cross-sensitivity of chemotherapy and disulfiram and use the double-bind to mitigate resistance, we also developed a game-theoretic mathematical modeling framework with parametrization performed using the “evolutionary game assay” technique, a direct measurement of payoff matrices that specify evolutionary games measured in cancer. Spheroids of varied initial frequencies of sensitive and resistant cells (100% monoculture; 75/25, 50/50, and 25/75 sensitive and resistant coculture) were treated with chemotherapy and disulfiram. The mathematical model was parameterized from the in vitro experimental data and as expected, treating with chemotherapy selects for resistant cells. However, disulfiram alone shifts the selection dynamics to favor sensitive cells. These modeling results predict the existence of a double-bind between chemotherapy and disulfiram where disulfiram selects for the sensitive subpopulation, which then re-sensitizes the spheroids to subsequent administration of chemotherapy. Importantly, the model predicts that the double-bind is non-symmetric and does not exist when treatments are given in combination. These predictions suggest the importance of timing/dosing strategies in which several schemes were further validated in vitro, confirming the superior efficacy of chemotherapy followed by disulfiram in blocking resistance emergence. This project integrates experimental data with mathematical modeling to identify a treatment double-bind in ER+ breast cancer. The integrative experimental-mathematical framework developed here has broad applicability in designing evolution-based or adaptive therapy treatment strategies across a wide range of cancer types. Citation Format: Rena Emond, Jeffrey West, Alexander Anderson, Andrea H. Bild. Disulfiram re-sensitizes ER+ breast cancer cells resistant to chemotherapy through an evolutionary double-bind [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3164.