RT Journal Article
SR Electronic
T1 Integrated time-course omics analysis distinguishes immediate therapeutic response from acquired resistance
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 136564
DO 10.1101/136564
A1 Genevieve Stein-O’Brien
A1 Luciane T Kagohara
A1 Sijia Li
A1 Manjusha Thakar
A1 Ruchira Ranaweera
A1 Hiroyuki Ozawa
A1 Haixia Cheng
A1 Michael Considine
A1 Alexander V Favorov
A1 Ludmila V Danilova
A1 Joseph A Califano
A1 Evgeny Izumchenko
A1 Daria A Gaykalova
A1 Christine H Chung
A1 Elana J Fertig
YR 2017
UL http://biorxiv.org/content/early/2017/07/07/136564.abstract
AB 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.