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Nat Commun. 2018 Aug 29;9(1):3501. doi: 10.1038/s41467-018-05742-z.

In vivo phosphoproteomics reveals kinase activity profiles that predict treatment outcome in triple-negative breast cancer.

Author information

1
Breast Cancer Clinical Research Unit, CNIO - Spanish National Cancer Research Center, 28029, Madrid, Spain.
2
Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands.
3
Netherlands Proteomics Center, Padualaan 8, 3584 CH, Utrecht, The Netherlands.
4
Medical Oncology, Hospital 12 de Octubre, Madrid, 28029, Spain.
5
Biobank, CNIO - Spanish National Cancer Research Center, Madrid, 28029, Spain.
6
Pathology Department, Hospital Universitario de Guadalajara, Guadalajara, 19002, Spain.
7
Experimental Therapeutics Group, VHIO - Vall d'Hebron Institute of Oncology, Barcelona, 08035, Spain.
8
Proteomics Unit, CNIO - Spanish National Cancer Research Center, Madrid, 28029, Spain.
9
Bioinformatics Unit, CNIO - Spanish National Cancer Research Center, Madrid, 28029, Spain.
10
Medical Oncology, Hospital Nacional Guillermo Almenara Irigoyen - ESSALUD, Lima, 15033, Peru.
11
Pathology Department, Hospital Universitario de Fuenlabrada, Fuenlabrada, 28942, Spain.
12
Medical Oncology, Hospital La Princesa, Madrid, 28006, Spain.
13
Genomics Unit, CNIC - Spanish National Center for Cardiovascular Research, Madrid, 28029, Spain.
14
Breast Cancer Clinical Research Unit, CNIO - Spanish National Cancer Research Center, 28029, Madrid, Spain. mquintela@cnio.es.
15
Medical Oncology, Hospital Universitario Fuenlabrada, Madrid, 28942, Spain. mquintela@cnio.es.
16
Medical Oncology, Hospital Universitario Quirón, Madrid, 28223, Spain. mquintela@cnio.es.

Abstract

Triple-negative breast cancer (TNBC) lacks prognostic and predictive markers. Here, we use high-throughput phosphoproteomics to build a functional TNBC taxonomy. A cluster of 159 phosphosites is upregulated in relapsed cases of a training set (n = 34 patients), with 11 hyperactive kinases accounting for this phosphoprofile. A mass-spectrometry-to-immunohistochemistry translation step, assessing 2 independent validation sets, reveals 6 kinases with preserved independent prognostic value. The kinases split the validation set into two patterns: one without hyperactive kinases being associated with a >90% relapse-free rate, and the other one showing ≥1 hyperactive kinase and being associated with an up to 9.5-fold higher relapse risk. Each kinase pattern encompasses different mutational patterns, simplifying mutation-based taxonomy. Drug regimens designed based on these 6 kinases show promising antitumour activity in TNBC cell lines and patient-derived xenografts. In summary, the present study elucidates phosphosites and kinases implicated in TNBC and suggests a target-based clinical classification system for TNBC.

PMID:
30158526
PMCID:
PMC6115463
DOI:
10.1038/s41467-018-05742-z
[Indexed for MEDLINE]
Free PMC Article

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