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• W3033242135 abstract "ABSTRACT Tumor heterogeneity is a primary cause of treatment failure and acquired resistance in cancer patients. Even in cancers driven by a single mutated oncogene, variability of targeted therapy response is observed. Additional genetic mutations can only partially explain this variability, leading to consideration of non-genetic factors, such as “stem-like” and “mesenchymal” phenotypic states, as critical contributors to tumor relapse and resistance. Here, we show that both genetic and non-genetic factors contribute to targeted drug-response variability in an experimental tumor heterogeneity model based on multiple versions and clonal sublines of PC9, the archetypal EGFR-mutant non-small cell lung cancer cell line. We observe significant drug-response variability across PC9 cell line versions, among sublines, and within sublines. To disentangle genetic, epigenetic, and stochastic components underlying this variability, we adopt a theoretical framework whereby distinct genetic states give rise to multiple epigenetic “basins of attraction”, across which cells can transition driven by stochastic factors such as gene expression noise and asymmetric cell division. Using mutational impact analysis, single-cell differential gene expression, and semantic similarity of gene ontology terms to connect genomics and transcriptomics, we establish a baseline of genetic differences explaining drug-response variability across PC9 cell line versions. In contrast, with the same approach, we conclude that in all but one of the clonal sublines, drug-response variability is due to epigenetic rather than genetic differences. Finally, using a clonal drug-response assay and stochastic simulations, we attribute drug-response variability within sublines to intracellular stochastic fluctuations and confirm that one subline likely contains a genetic resistance mutation that emerged in the absence of selective pressures. We propose that a theoretical framework deconvolving the complex interplay among genetic, epigenetic, and stochastic sources of intratumoral heterogeneity will lead to novel therapeutic strategies to combat tumor relapse and resistance." @default.
• W3033242135 created "2020-06-12" @default.
• W3033242135 creator A5003212140 @default.
• W3033242135 creator A5006697675 @default.
• W3033242135 creator A5010400772 @default.
• W3033242135 creator A5010970756 @default.
• W3033242135 creator A5061250244 @default.
• W3033242135 creator A5070903980 @default.
• W3033242135 date "2020-06-05" @default.
• W3033242135 modified "2023-10-18" @default.
• W3033242135 title "A unifying framework disentangles genetic, epigenetic, and stochastic sources of drug-response variability in an<i>in vitro</i>model of tumor heterogeneity" @default.
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