Abstract 2674: Cellular plasticity facilitates therapy resistance through enhancing adaptability

Abstract In oncology, patients treated with targeted therapies often have strong and durable responses early in treatment; however, the development of resistance hinders long-term therapeutic benefit. A subset of tumor cells can develop resistance, often from both genetic and non-genetic mechanisms through gradual, multi-step resistance. Nonetheless, predicting which cells will evolve to become resistant, and strategies to suppress adaptability contributing to resistance remain unknown. While resistance may emerge in cells harboring driver mutations, the adaptation process necessitates substantial modifications to the phenotype facilitated by cellular plasticity. Therefore, plasticity serves as a crucial facilitator of resistance by enhancing adaptability, rather than functioning as a direct cause of resistance. We hypothesize that the direct selection for therapy resistance leads to indirect selection for enhanced plasticity. We propose that as treatment selects for drug-resistant phenotypes, concurrent selection for cells exhibiting greater adaptability occurs. Thus, enhanced plasticity is indirectly favored during selection for drug resistance. We have found strong support for this hypothesis through in silico modeling, with subsequent validation through functional assays. In our functional assays, we utilize the H3122 cell line derived from a patient with ALK+ non-small cell lung cancer (NSCLC) to model targeted therapy resistance. This well-studied model effectively mimics the initial responsiveness and subsequent resistance observed in clinical settings. Utilizing single-cell sorting and the expansion of clonal isolates from the parental H3122 population, we identified heterogeneity in the ability to adapt where subgroups exhibited a range of high adaptation potential (HAP) to low adaptation potential (LAP) based on their response to numerous independent stressors, including targeted ALK inhibitors. We have found that therapeutic stressors lead to selection of subpopulations with higher adaptability potential, enriching for a more lethal subgroup than the original tumor. HAP cells display increased multi-drug resistance and metastatic potential compared to LAP cells. HAP cells are significantly enriched in plasticity-related pathways overlapping with those found in cells that have developed strong resistance to ALK inhibitors. In subcutaneous tumor models, LAP cells show a 1, 000-fold reduction in tumor burden, while HAP cells develop resistance. Our findings suggest that disrupting cellular adaptability can prevent resistance, maintaining cells in a therapy-sensitive state. This approach shifts the focus from killing tumor cells to blocking their ability to adapt, opening up a novel angle for overcoming resistance. Addressing adaptability reveals intervention points that conventional strategies might overlook, offering new, proactive strategies in cancer treatment. Citation Format: Alicia Bjornberg, Xierali Aobuli, Matthew Froid, Rowan Barker-Clarke, Jeff Maltas, Jacob Scott, Berkley Gryder, David Bassanta, Alexander Anderson, Virginia Turati, Andriy Marusyk. Cellular plasticity facilitates therapy resistance through enhancing adaptability. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2674.