TY - JOUR
T1 - In vivo phosphoproteomics reveals kinase activity profiles that predict treatment outcome in triple-negative breast cancer
AU - Zagorac, Ivana
AU - Fernandez-Gaitero, Sara
AU - Penning, Renske
AU - Post, Harm
AU - Bueno, Maria J
AU - Mouron, Silvana
AU - Manso, Luis
AU - Morente, Manuel M
AU - Alonso, Soledad
AU - Serra, Violeta
AU - Muñoz, Javier
AU - Gómez-López, Gonzalo
AU - Lopez-Acosta, Jose Francisco
AU - Jimenez-Renard, Veronica
AU - Gris-Oliver, Albert
AU - Al-Shahrour, Fatima
AU - Piñeiro-Yañez, Elena
AU - Montoya-Suarez, Jose Luis
AU - Apala, Juan V
AU - Moreno-Torres, Amalia
AU - Colomer, Ramon
AU - Dopazo, Ana
AU - Heck, Albert J R
AU - Altelaar, Maarten
AU - Quintela-Fandino, Miguel
PY - 2018/8/29
Y1 - 2018/8/29
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-018-05742-z
DO - 10.1038/s41467-018-05742-z
M3 - Article
C2 - 30158526
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3501
ER -
