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

Autor: Stein-O'Brien G; Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA.; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA., Kagohara LT; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA., Li S; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA., Thakar M; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA., Ranaweera R; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.; Department of Head and Neck-Endocrine Oncology, Moffitt Cancer Center, Tampa, FL, USA., Ozawa H; Department of Otorhinolaryngology-Head and Neck Surgery, Keio University School of Medicine, Tokyo, Japan., Cheng H; Department of Surgery - Otolaryngology-Head and Neck Surgery, University of Utah, |Salt Lake City, UT, USA., Considine M; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA., Schmitz S; Head and Neck Surgery Unit, St Luc University Hospital, Brussels, Belgium., Favorov AV; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.; Laboratory of Systems Biology and Computational Genetics, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia., Danilova LV; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.; Laboratory of Systems Biology and Computational Genetics, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia., Califano JA; Department of Surgery, UC San Diego Moores Cancer Center, La Jolla, CA, USA., Izumchenko E; Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University, Baltimore, MD, USA., Gaykalova DA; Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University, Baltimore, MD, USA., Chung CH; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Christine.Chung@moffitt.org.; Department of Head and Neck-Endocrine Oncology, Moffitt Cancer Center, Tampa, FL, USA. Christine.Chung@moffitt.org., Fertig EJ; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. ejfertig@jhmi.edu.
Jazyk: angličtina
Zdroj: Genome medicine [Genome Med] 2018 May 23; Vol. 10 (1), pp. 37. Date of Electronic Publication: 2018 May 23.
DOI: 10.1186/s13073-018-0545-2
Abstrakt: 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 epigenetic alterations associated with resistance that have concordant expression changes are hypothesized to stabilize the resistant phenotype. These genes include FGFR1, which was associated with EGFR inhibitors resistance previously. Thus, integrated omics analysis distinguishes the timing of molecular drivers of resistance. This understanding of the time course progression of molecular changes in acquired resistance is important for the development of alternative treatment strategies that would introduce appropriate selection of new drugs to treat cancer before the resistant phenotype develops.
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje