TY - JOUR T1 - Integrated time-course omics analysis distinguishes immediate therapeutic response from acquired resistance JF - bioRxiv DO - 10.1101/136564 SP - 136564 AU - Genevieve Stein-O’Brien AU - Luciane T Kagohara AU - Sijia Li AU - Manjusha Thakar AU - Ruchira Ranaweera AU - Hiroyuki Ozawa AU - Haixia Cheng AU - Michael Considine AU - Alexander V Favorov AU - Ludmila V Danilova AU - Joseph A Califano AU - Evgeny Izumchenko AU - Daria A Gaykalova AU - Christine H Chung AU - Elana J Fertig Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/07/06/136564.abstract N2 - Most cancers acquire resistance to targeted therapeutics. Knowing the timing of molecular changes responsible for the development of acquired resistance can enable optimization of alterations to patients’ treatments. Clinically, acquired therapeutic resistance can only be studied at a single time point in resistant tumors. To determine the dynamics of these molecular changes, we obtained high throughput omics data weekly during the development of cetuximab resistance in a head and neck cancer model. An unsupervised algorithm, CoGAPS, quantified the evolving transcriptional and epigenetic changes. Further 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 resulted from immediate therapeutic response and resistance whereas epigenetic alterations only occurred with resistance. Integrated analysis demonstrated delayed onset of changes in DNA methylation relative to transcription, suggesting that resistance was stabilized epigenetically. Genes with epigenetic alterations associated with resistance that had concordant expression changes were hypothesized to stabilize resistance. These genes include FGFR1, which was associated with EGFR inhibitor resistance previously. Thus, integrated omics analysis distinguishes the timing of molecular drivers of resistance. ER -