Abstract Therapeutic resistance to chemotherapy is frequently the proximate cause of increased tumor burden, cancer treatment failure, and ultimately, patient mortality. The most successful therapy strategy derived from evolutionary practices to date, Adaptive Therapy (AT), leverages the fitness cost of developing therapeutic resistance. AT avoids treating cancer cells with the Maximum Tolerated Dose (MTD) of therapeutic drugs and instead incorporates a series of adaptive dosing schedules. Treatment-sensitive cells are bolstered by modulating or pausing treatment to out-compete and suppress treatment-resistant cell growth. We are evaluating AT for the first time in colorectal cancer, using a syngeneic orthotopic xenograft model. This work represents several key advances: it is the first to longitudinally and non-invasively track sensitive and resistant clones in vivo, to evaluate adaptive therapy in an immunocompetent mouse model, to incorporate multi-drug treatment regimens, and to integrate a targeted therapeutic agent. The dual-bioluminescent sensitive and resistant CT26 cell lines developed for this study allow real-time visualization and quantification of each population throughout tumor progression and treatment. Together, these advances establish a robust and clinically relevant platform for characterizing resistance dynamics and refining adaptive therapy strategies aimed at improving treatment outcomes in colorectal cancer. Citation Format: Harley I. Richker, Bailey Sierra Kane, Gissel Marquez Alcaraz, Ellie Pahl, Ryan Carr, Nagarajan Kannan, Carlo C. Maley. Harnessing clonal dynamics to overcome resistance: An adaptive therapy framework in colorectal cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 702.
Richker et al. (Fri,) studied this question.