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

Nature Communications
Ivana ZagoracMiguel Quintela-Fandino

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.

References

Sep 13, 2001·Proceedings of the National Academy of Sciences of the United States of America·T SørlieA L Børresen-Dale
Apr 2, 2005·Breast Cancer Research and Treatment·Shanu ModiClifford A Hudis
Oct 4, 2005·Proceedings of the National Academy of Sciences of the United States of America·Aravind SubramanianJill P Mesirov
Mar 9, 2007·Nature Biotechnology·Ramars AmanchyAkhilesh Pandey
Jun 3, 2008·Annals of Oncology : Official Journal of the European Society for Medical Oncology·M CristofanilliG N Hortobagyi
Feb 24, 2009·Proteomics·Tine E ThingholmMartin R Larsen
Apr 21, 2009·Nature Methods·Jacek R WiśniewskiMatthias Mann
Oct 8, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Corey SpeersPowel Brown
Oct 17, 2009·Expert Review of Neurotherapeutics·Richard B Lipton, Min Kyung Chu
Mar 17, 2010·Clinical & Translational Oncology : Official Publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico·José Luis Pérez-GraciaIgnacio Melero Bermejo
May 25, 2010·Nature Structural & Molecular Biology·Yonathan Lissanu DeribeIvan Dikic
Nov 12, 2010·The New England Journal of Medicine·William D FoulkesJorge S Reis-Filho
Mar 19, 2011·Journal of Proteome Research·Christian K FreseShabaz Mohammed
Jun 3, 2011·The Journal of Clinical Investigation·Brian D LehmannJennifer A Pietenpol
Feb 9, 2012·Cell Research·Alicia A MidlandGary L Johnson
Mar 27, 2012·The Journal of Clinical Investigation·Cynthia X MaHelen Piwnica-Worms
Jun 23, 2012·Nature·Matthew J EllisElaine R Mardis
Jun 23, 2012·Nature·Philip J StephensMichael R Stratton
Jun 23, 2012·Nature·Shantanu BanerjiMatthew Meyerson
Jun 27, 2012·The Journal of Biological Chemistry·Jeffry L DeanErik S Knudsen
Sep 25, 2012·Nature·UNKNOWN Cancer Genome Atlas Network
Dec 5, 2012·Nature Reviews. Genetics·A F Maarten AltelaarAlbert J R Heck
Jan 16, 2013·The British Journal of Surgery·S KashiwagiK Hirakawa
Feb 12, 2013·Nature Biotechnology·Kristian CibulskisGad Getz
Apr 17, 2013·BMC Bioinformatics·Edward Y ChenAvi Ma'ayan
Jan 21, 2014·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Anthony TolcherLee S Rosen
May 30, 2014·Nature·Min-Sik KimAkhilesh Pandey
Sep 12, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Matthew D BursteinPowel H Brown
Mar 3, 2015·Laboratory Investigation; a Journal of Technical Methods and Pathology·Sibylle GündischGianni Bussolati

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Citations

Dec 20, 2018·Molecular & Cellular Proteomics : MCP·Karsten KrugD R Mani
Aug 15, 2019·Bioinformatics·Hongyang Li, Yuanfang Guan
Oct 1, 2020·The Analyst·Mustafa Gani SürmenNesrin Emekli
Feb 11, 2020·Frontiers in Cell and Developmental Biology·Joseph Parsons, Chiara Francavilla
Jun 4, 2020·Clinical Proteomics·Andrew MacklinThomas Kislinger
Apr 17, 2019·Cancer Research·Dipali Sharma
Jan 28, 2021·Journal of Materials Chemistry. B, Materials for Biology and Medicine·Shuang YanYao Wu
Mar 1, 2019·Molecular & Cellular Proteomics : MCP·Karsten KrugD R Mani
Mar 22, 2021·Cardiovascular Research·Sina SafabakhshZachary Laksman
Jul 23, 2021·Molecular Omics·Sara HamzelouPaul A Haynes
Jun 17, 2020·Journal of Proteome Research·Zhiyuan WangLinshi Wu
May 13, 2020·Journal of Proteome Research·Anton IliukW Andy Tao
Sep 10, 2021·Frontiers in Cell and Developmental Biology·Weipeng ZhaoZhongsheng Tong

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Datasets Mentioned

BETA
PXD008012The

Methods Mentioned

BETA
xenografts
biopsy
transfection
acetylation
protein assay
DNA Assay

Software Mentioned

Ensembl Effect Predictor ( VEP
Ensembl
RUbioSeq
Val
gene Set Enrichment Analysis ( GSEA ) - set enrichment analysi...
PolyPhen
GENE
MuTect
Perseus
SIFT

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