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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.

SUBMITTER: Huang KL

PROVIDER: S-EPMC5379071 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Proteogenomic integration reveals therapeutic targets in breast cancer xenografts.

Huang Kuan-Lin KL Li Shunqiang S Mertins Philipp P Cao Song S Gunawardena Harsha P HP Ruggles Kelly V KV Mani D R DR Clauser Karl R KR Tanioka Maki M Usary Jerry J Kavuri Shyam M SM Xie Ling L Yoon Christopher C Qiao Jana W JW Wrobel John J Wyczalkowski Matthew A MA Erdmann-Gilmore Petra P Snider Jacqueline E JE Hoog Jeremy J Singh Purba P Niu Beifung B Guo Zhanfang Z Sun Sam Qiancheng SQ Sanati Souzan S Kawaler Emily E Wang Xuya X Scott Adam A Ye Kai K McLellan Michael D MD Wendl Michael C MC Malovannaya Anna A Held Jason M JM Gillette Michael A MA Fenyö David D Kinsinger Christopher R CR Mesri Mehdi M Rodriguez Henry H Davies Sherri R SR Perou Charles M CM Ma Cynthia C Reid Townsend R R Chen Xian X Carr Steven A SA Ellis Matthew J MJ Ding Li L

Nature communications 20170328

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 analys ...[more]

PMID: 28348404

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Project description:Huang K, Li S, Mertins P, Cao S, Gunawardena HP, Ruggles KV, et al., (2017) Nature Communications | 8:14864 | DOI: 10.1038/ncomms14864 | <a href="http://www.nature.com/articles/ncomms14864" target="_blank">http://www.nature.com/articles/ncomms14864</a>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.Additional supplementary data sets, provided below Huang_Proteome_Peptide_Spectrum_Match_Results_SpectrumMill is the Proteome Peptide Spectrum Match reports exported from Spectrum Mill for each of the iTRAQ4 experiments, including the RefSeq FASTA file used for searches, and a Spectrum Mill quality metrics report.<ul><li>Dataset imported into MassIVE from <a href="https://cptac-data-portal.georgetown.edu/cptac/s/S032">https://cptac-data-portal.georgetown.edu/cptac/s/S032</a> on 08/28/19</li></ul>

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Proteogenomic integration reveals therapeutic targets in breast cancer xenografts.

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Proteogenomic integration reveals therapeutic targets in breast cancer xenografts.

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