Proteogenomic integration reveals therapeutic targets in breast cancer xenografts
| Autor: | Shyam M. Kavuri, Steven A. Carr, Beifang Niu, Shunqiang Li, Matthew A. Wyczalkowski, David Fenyö, Jason M. Held, Jerry Usary, Adam D. Scott, Kuan-lin Huang, Philipp Mertins, Souzan Sanati, Mehdi Mesri, Harsha P. Gunawardena, Kai Ye, Cynthia X. Ma, John A. Wrobel, Matthew J. Ellis, Li Ding, Purba Singh, D. R. Mani, Jeremy Hoog, Jacqueline E. Snider, Song Cao, Ling Xie, Raymond R. Townsend, Xuya Wang, Sherri R. Davies, Jana W. Qiao, Emily Kawaler, Kelly V. Ruggles, Christopher R. Kinsinger, Anna Malovannaya, Henry Rodriguez, Maki Tanioka, Charles M. Perou, Zhanfang Guo, Petra Erdmann-Gilmore, Christopher J. Yoon, Xian Chen, Karl R. Clauser, Sam Q. Sun, Michael A. Gillette, Michael C. Wendl, Michael D. McLellan |
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| Přispěvatelé: | Koch Institute for Integrative Cancer Research at MIT, Carr, Steven A |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Multidisciplinary biology Science Quantitative proteomics Druggability General Physics and Astronomy General Chemistry Computational biology Proteogenomics Proteomics General Biochemistry Genetics and Molecular Biology Receptor tyrosine kinase 3. Good health 03 medical and health sciences 030104 developmental biology Proteome Immunology biology.protein Technology Platforms ARAF PI3K/AKT/mTOR pathway |
| Zdroj: | Nature Communications, Vol 8, Iss 1, Pp 1-17 (2017) Nature |
| ISSN: | 2041-1723 |
| Popis: | Recent advances in mass spectrometry (MS) have enabled extensive analysis of cancer proteomes. Here, we employed quantitative proteomics to profile protein expression across 24 breast cancer patient-derived xenograft (PDX) models. Integrated proteogenomic analysis shows positive correlation between expression measurements from transcriptomic and proteomic analyses; further, gene expression-based intrinsic subtypes are largely re-capitulated using non-stromal protein markers. Proteogenomic analysis also validates a number of predicted genomic targets in multiple receptor tyrosine kinases. However, several protein/phosphoprotein events such as overexpression of AKT proteins and ARAF, BRAF, HSP90AB1 phosphosites are not readily explainable by genomic analysis, suggesting that druggable translational and/or post-translational regulatory events may be uniquely diagnosed by MS. Drug treatment experiments targeting HER2 and components of the PI3K pathway supported proteogenomic response predictions in seven xenograft models. Our study demonstrates that MS-based proteomics can identify therapeutic targets and highlights the potential of PDX drug response evaluation to annotate MS-based pathway activities. National Cancer Institute (U.S.) (Grant R01CA180006) |
| Databáze: | OpenAIRE |
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