TY - JOUR
T1 - Proteogenomic integration reveals therapeutic targets in breast cancer xenografts
AU - Huang, Kuan Lin
AU - Li, Shunqiang
AU - Mertins, Philipp
AU - Cao, Song
AU - Gunawardena, Harsha P.
AU - Ruggles, Kelly V.
AU - Mani, D. R.
AU - Clauser, Karl R.
AU - Tanioka, Maki
AU - Usary, Jerry
AU - Kavuri, Shyam M.
AU - Xie, Ling
AU - Yoon, Christopher
AU - Qiao, Jana W.
AU - Wrobel, John
AU - Wyczalkowski, Matthew A.
AU - Erdmann-Gilmore, Petra
AU - Snider, Jacqueline E.
AU - Hoog, Jeremy
AU - Singh, Purba
AU - Niu, Beifung
AU - Guo, Zhanfang
AU - Sun, Sam Qiancheng
AU - Sanati, Souzan
AU - Kawaler, Emily
AU - Wang, Xuya
AU - Scott, Adam
AU - Ye, Kai
AU - McLellan, Michael D.
AU - Wendl, Michael C.
AU - Malovannaya, Anna
AU - Held, Jason M.
AU - Gillette, Michael A.
AU - Fenyö, David
AU - Kinsinger, Christopher R.
AU - Mesri, Mehdi
AU - Rodriguez, Henry
AU - Davies, Sherri R.
AU - Perou, Charles M.
AU - Ma, Cynthia
AU - Reid Townsend, R.
AU - Chen, Xian
AU - Carr, Steven A.
AU - Ellis, Matthew J.
AU - Ding, Li
N1 - Funding Information:
This work was supported by the National Cancer Institute grants U24CA160035 to Reid Townsend/Matthew Ellis/Xian Chen, Siteman Cancer Center grant (NCI P30 CA091842) to Reid Townsend, U24CA160034 to Steven Carr, R01CA180006 to L.D., National Human Genome Research Institute grant U01HG006517 to L.D., the NCI Breast SPORE program (P50-CA58223-09A1), R01CA195754-01, by the Breast Cancer Research Foundation to Charles Perou and Komen CCR award to S.M.K. (CCR16380599).
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/3/28
Y1 - 2017/3/28
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85016396817&partnerID=8YFLogxK
U2 - 10.1038/ncomms14864
DO - 10.1038/ncomms14864
M3 - Article
C2 - 28348404
AN - SCOPUS:85016396817
SN - 2041-1723
VL - 8
JO - Nature communications
JF - Nature communications
M1 - 14864
ER -