Proteogenomic integration reveals therapeutic targets in breast cancer xenografts

Author:

Huang Kuan-lin,Li Shunqiang,Mertins Philipp,Cao Song,Gunawardena Harsha P.,Ruggles Kelly V.ORCID,Mani D. R.,Clauser Karl R.,Tanioka Maki,Usary Jerry,Kavuri Shyam M.,Xie Ling,Yoon Christopher,Qiao Jana W,Wrobel John,Wyczalkowski Matthew A.ORCID,Erdmann-Gilmore Petra,Snider Jacqueline E.,Hoog Jeremy,Singh Purba,Niu Beifang,Guo Zhanfang,Sun Sam Qiancheng,Sanati Souzan,Kawaler Emily,Wang Xuya,Scott Adam,Ye Kai,McLellan Michael D.,Wendl Michael C.,Malovannaya Anna,Held Jason M.,Gillette Michael A.,Fenyö David,Kinsinger Christopher R.,Mesri Mehdi,Rodriguez Henry,Davies Sherri R.,Perou Charles M.,Ma Cynthia,Reid Townsend R.,Chen Xian,Carr Steven A.,Ellis Matthew J.,Ding LiORCID

Abstract

AbstractRecent 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.

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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