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

• Published in: Nature communications Vol. 9; no. 1; pp. 3501 - 15
• Main Authors: Zagorac, Ivana, Fernandez-Gaitero, Sara, Penning, Renske, Post, Harm, Bueno, Maria J., Mouron, Silvana, Manso, Luis, Morente, Manuel M., Alonso, Soledad, Serra, Violeta, Muñoz, Javier, Gómez-López, Gonzalo, Lopez-Acosta, Jose Francisco, Jimenez-Renard, Veronica, Gris-Oliver, Albert, Al-Shahrour, Fatima, Piñeiro-Yañez, Elena, Montoya-Suarez, Jose Luis, Apala, Juan V., Moreno-Torres, Amalia, Colomer, Ramon, Dopazo, Ana, Heck, Albert J. R., Altelaar, Maarten, Quintela-Fandino, Miguel
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 29.08.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/51; 13/95; 45/23; 631/154/53/2422; 631/337/475; 631/67/1059/602; 631/67/1347; 64/110; 64/60; 82/58; 96/95; Anticancer properties; Breast cancer; Cancer; Cell Line, Tumor; Female; Humanities and Social Sciences; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Kinases; Mass Spectrometry; multidisciplinary; Patients; Phosphoproteins - metabolism; Phosphotransferases - metabolism; Science; Science (multidisciplinary); Spectrometry; Taxonomy; Treatment Outcome; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - mortality; Xenografts; Xenotransplantation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-05742-z

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. Triple-negative breast cancer (TNBC) lacks prognostic and predictive markers. Here, the authors use phosphoproteomics to define kinases with distinct activity profiles in TNBC, demonstrating their prognostic value as well as their utility for simplifying TNBC classification and designing drug regimens.