Abstract IA018: Rare cell variability and drug resistance in cancer

Abstract

Abstract Even within a clonal cancer, individual cells have different responses to drugs; while some cells may be sensitive to a therapy and die, other cells from the same tumor can be resistant and continue to grow. Methods such as single-cell RNA-sequencing provide a snapshot into the underlying molecular variability responsible for different single-cell phenotypes. However, the missing dimension from such end-point based methods is time. Single-cell RNA-seq provides just one time point of gene expression, but does not capture the dynamics of how gene expression states change with time. In this talk, I will present an experimental and computational approach to capture the timescales of gene expression states and their relationship to therapy resistance. Here, we leverage high-throughput cellular barcoding and single-cell RNA-sequencing to track gene expression for thousands of cells and to predict the time for which these gene expression states persist in single cells. These techniques uncover the TGFB pathway as an inducer of the gene expression states that prime melanoma cells for resistance to BRAF/MEK inhibitors. Further, I will present a strategy for overcoming resistance through targeting the pre-existing cellular states that ultimately give rise to drug resistance. Citation Format: Sydney Shaffer. Rare cell variability and drug resistance in cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr IA018.