Abstract B012: A review of experimental evidence for cost of therapeutic resistance in cancer

Abstract Emergence of therapeutic resistance remains a relevant clinical challenge in cancer treatment, contributing to treatment failure, disease relapse, and overall poor prognosis. Adaptive therapy (AT) aims to address this issue by guiding clonal evolution to promote competition between therapy-sensitive and therapy-resistant clones, thereby allowing for long-term control of tumor burden. AT relies upon the assumption that resistance acquisition is an evolutionary tradeoff that confers a net fitness disadvantage in an environment lacking sufficient selective pressure from therapy. Despite promising preclinical studies and corroborative mathematical models, no comprehensive literature review has been conducted on the available experimental evidence regarding the cost of resistance in cancer to date. Therefore, we aim to conduct a systematic review of the cost of resistance in in-vitro and in-vivo cancer models. We searched the databases Scopus (all time), PubMed Central (all time), and Google Scholar (all time), as well as the reference lists of selected literature, for peer-reviewed papers that fulfilled the following selection criteria: (i) experiments depict direct competition, (ii) between therapy-resistant and therapy-sensitive clones, (iii) in a therapy-free environment. Information from selected papers, including the biological model, resistance characteristics, and results of the competitive experiment, was evaluated by the research team. Preliminary results demonstrate consistency between in-vitro and in-vivo trials. In addition to simple winner and loser dynamics, we identify four main categories of fitness consequences: intrinsic cost, intrinsic benefit, competition-dependent benefit (“farming”), and collateral sensitivity. The specific mechanism of resistance appears to be the greatest predictor of costliness, though it was not included in all experiments reviewed. We find substantial evidence to support the cost of resistance in certain, but not all, models of resistant cancer. We also identify a significant gap in the understanding of the fitness consequences of other mechanisms of resistance, such as cellular senescence or density-dependent effects. Understanding which acquired resistance characteristics can be exploited therapeutically with AT will prove invaluable for designing future preclinical trials. Citation Format: Bailey Kane, Lauren Mestas, Tiara Soesilo, Madds Garza, Meghan Hufford, Jaqueline Dominguez, Harley Richker, Carlo C. Maley. A review of experimental evidence for cost of therapeutic resistance in cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Cancer Evolution: The Dynamics of Progression and Persistence; 2025 Dec 4-6; Albuquerque, NM. Philadelphia (PA): AACR; Cancer Res 2025;85(23_Suppl):Abstract nr B012.