Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-05742-z
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Funding
- AECC Scientific Foundation Beca de Retorno 2010
- ISCIII [PIE15/00068]
- La Caixa PhD Fellowship, 2011
- FPI grant [SEV-2015-0510-16-6]
- Miguel Servet Program [CP14/00228]
- PRIME-XS project [262067]
- European Union Seventh Framework Program
- project Proteins At Work [184.032.201]
- program of the Netherlands Proteomics Centre by the Netherlands Organisation for Scientific Research (NWO)
- NWO through a VIDI grant [723.012.102]
- [FIS PI10/00288]
- [FIS PI13/00430]
- [FIS PI11-00832]
- [FIS PI14-00726]
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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.
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