Integrated time course omics analysis distinguishes immediate therapeutic response from acquired resistance

作者：Genevieve Stein-O’Brien, Luciane T. Kagohara, Sijia Li, Manjusha Thakar, Ruchira S. Ranaweera, Hiroyuki Ozawa, Haixia Cheng, Michael Considine, Sandra Schmitz, Alexander V. Favorov, Ludmila Danilova, Joseph A. Califano, Evgeny Izumchenko, Daria A. Gaykalova, Christine H. Chung, Elana J. Fertig · 发表于：Genome Medicine · 年份：2018 · DOI：10.1186/s13073-018-0545-2 · 被引用次数：33 · 研究领域：Cancer Genomics and Diagnostics、Epigenetics and DNA Methylation、Fibroblast Growth Factor Research

BACKGROUND: Targeted therapies specifically act by blocking the activity of proteins that are encoded by genes critical for tumorigenesis. However, most cancers acquire resistance and long-term disease remission is rarely observed. Understanding the time course of molecular changes responsible for the development of acquired resistance could enable optimization of patients' treatment options. Clinically, acquired therapeutic resistance can only be studied at a single time point in resistant tumors. METHODS: To determine the dynamics of these molecular changes, we obtained high throughput omics data (RNA-sequencing and DNA methylation) weekly during the development of cetuximab resistance in a head and neck cancer in vitro model. The CoGAPS unsupervised algorithm was used to determine the dynamics of the molecular changes associated with resistance during the time course of resistance development. RESULTS: CoGAPS was used to quantify the evolving transcriptional and epigenetic changes. Applying a PatternMarker statistic to the results from CoGAPS enabled novel heatmap-based visualization of the dynamics in these time course omics data. We demonstrate that transcriptional changes result from immediate therapeutic response or resistance, whereas epigenetic alterations only occur with resistance. Integrated analysis demonstrates delayed onset of changes in DNA methylation relative to transcription, suggesting that resistance is stabilized epigenetically. CONCLUSIONS: Genes with e...