title: Proteogenomic integration reveals therapeutic targets in breast cancer xenografts.
abstract: 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.
authors.affiliation: Department of Medicine, Washington University in St. Louis, St. Louis, Missouri 63108, USA.|McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri 63108, USA.
authors.forename: Kuan-Lin
authors.initials: KL
authors.lastname: Huang
authors.affiliation: Department of Medicine, Washington University in St. Louis, St. Louis, Missouri 63108, USA.
authors.forename: Shunqiang
authors.initials: S
authors.lastname: Li
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
authors.forename: Philipp
authors.initials: P
authors.lastname: Mertins
authors.affiliation: McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri 63108, USA.
authors.forename: Song
authors.initials: S
authors.lastname: Cao
authors.affiliation: Department of Biochemistry &Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Harsha P
authors.initials: HP
authors.lastname: Gunawardena
authors.affiliation: Center for Health Informatics and Bioinformatics, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Kelly V
authors.identifier: 0000-0002-0152-0863
authors.initials: KV
authors.lastname: Ruggles
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Mani
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
authors.forename: Karl R
authors.initials: KR
authors.lastname: Clauser
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Maki
authors.initials: M
authors.lastname: Tanioka
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Jerry
authors.initials: J
authors.lastname: Usary
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Shyam M
authors.initials: SM
authors.lastname: Kavuri
authors.affiliation: Department of Biochemistry &Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Xie
authors.affiliation: Department of Medicine, Washington University in St. Louis, St. Louis, Missouri 63108, USA.|McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri 63108, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Yoon
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
authors.forename: Jana W
authors.initials: JW
authors.lastname: Qiao
authors.affiliation: Department of Biochemistry &Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: John
authors.initials: J
authors.lastname: Wrobel
authors.affiliation: McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri 63108, USA.
authors.forename: Matthew A
authors.identifier: 0000-0003-4197-551X
authors.initials: MA
authors.lastname: Wyczalkowski
authors.affiliation: Department of Medicine, Washington University in St. Louis, St. Louis, Missouri 63108, USA.
authors.forename: Petra
authors.initials: P
authors.lastname: Erdmann-Gilmore
authors.affiliation: Department of Medicine, Washington University in St. Louis, St. Louis, Missouri 63108, USA.
authors.forename: Jacqueline E
authors.initials: JE
authors.lastname: Snider
authors.affiliation: Department of Medicine, Washington University in St. Louis, St. Louis, Missouri 63108, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hoog
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Purba
authors.initials: P
authors.lastname: Singh
authors.affiliation: McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri 63108, USA.
authors.forename: Beifung
authors.initials: B
authors.lastname: Niu
authors.affiliation: Department of Medicine, Washington University in St. Louis, St. Louis, Missouri 63108, USA.
authors.forename: Zhanfang
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Department of Medicine, Washington University in St. Louis, St. Louis, Missouri 63108, USA.|McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri 63108, USA.
authors.forename: Sam Qiancheng
authors.initials: SQ
authors.lastname: Sun
authors.affiliation: Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, Missouri 63108, USA.
authors.forename: Souzan
authors.initials: S
authors.lastname: Sanati
authors.affiliation: Center for Health Informatics and Bioinformatics, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Kawaler
authors.affiliation: Center for Health Informatics and Bioinformatics, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Xuya
authors.initials: X
authors.lastname: Wang
authors.affiliation: McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri 63108, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Scott
authors.affiliation: McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri 63108, USA.|Department of Genetics, Washington University in St. Louis, St. Louis, Missouri 63108, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Ye
authors.affiliation: McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri 63108, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: McLellan
authors.affiliation: McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri 63108, USA.|Department of Genetics, Washington University in St. Louis, St. Louis, Missouri 63108, USA.|Department of Mathematics, Washington University in St. Louis, St. Louis, Missouri 63108, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Wendl
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas 77030, USA.|Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Malovannaya
authors.affiliation: Department of Medicine, Washington University in St. Louis, St. Louis, Missouri 63108, USA.|Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri 63108, USA.|Department of Anesthesiology, Washington University in St. Louis, St. Louis, Missouri 63108, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Held
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gillette
authors.affiliation: Center for Health Informatics and Bioinformatics, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: David
authors.initials: D
authors.lastname: Fenyö
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Kinsinger
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Mesri
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Henry
authors.initials: H
authors.lastname: Rodriguez
authors.affiliation: Department of Medicine, Washington University in St. Louis, St. Louis, Missouri 63108, USA.
authors.forename: Sherri R
authors.initials: SR
authors.lastname: Davies
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.affiliation: Department of Medicine, Washington University in St. Louis, St. Louis, Missouri 63108, USA.|Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri 63108, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Ma
authors.affiliation: Department of Medicine, Washington University in St. Louis, St. Louis, Missouri 63108, USA.|Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri 63108, USA.
authors.forename: R
authors.initials: R
authors.lastname: Reid Townsend
authors.affiliation: Department of Biochemistry &Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Xian
authors.initials: X
authors.lastname: Chen
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Carr
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Ellis
authors.affiliation: Department of Medicine, Washington University in St. Louis, St. Louis, Missouri 63108, USA.|McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri 63108, USA.|Department of Genetics, Washington University in St. Louis, St. Louis, Missouri 63108, USA.|Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri 63108, USA.
authors.forename: Li
authors.identifier: 0000-0003-1517-2975
authors.initials: L
authors.lastname: Ding
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000628:therapy*; D005260:Female; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D010766:Phosphorylation; D000071696:Proteogenomics; D015398:Signal Transduction; D059467:Transcriptome / Q000235:genetics; D023041:Xenograft Model Antitumor Assays