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Systemic analysis of tyrosine kinase signaling reveals a common adaptive response program in a HER2-positive breast cancer.
Schwill, Martin; Tamaskovic, Rastislav; Gajadhar, Aaron S; Kast, Florian; White, Forest M; Plückthun, Andreas.
Afiliación
  • Schwill M; Department of Biochemistry, University of Zurich, Winterthurerstr. 190, 8057 Zurich, Switzerland.
  • Tamaskovic R; Department of Biochemistry, University of Zurich, Winterthurerstr. 190, 8057 Zurich, Switzerland.
  • Gajadhar AS; Department of Biological Engineering, Koch Institute for Integrative Cancer Research, Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Kast F; Department of Biochemistry, University of Zurich, Winterthurerstr. 190, 8057 Zurich, Switzerland.
  • White FM; Department of Biological Engineering, Koch Institute for Integrative Cancer Research, Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Plückthun A; Department of Biochemistry, University of Zurich, Winterthurerstr. 190, 8057 Zurich, Switzerland. plueckthun@bioc.uzh.ch.
Sci Signal ; 12(565)2019 01 22.
Article en En | MEDLINE | ID: mdl-30670633
Drug-induced compensatory signaling and subsequent rewiring of the signaling pathways that support cell proliferation and survival promote the development of acquired drug resistance in tumors. Here, we sought to analyze the adaptive kinase response in cancer cells after distinct treatment with agents targeting human epidermal growth factor receptor 2 (HER2), specifically those that induce either only temporary cell cycle arrest or, alternatively, apoptosis in HER2-overexpressing cancers. We compared trastuzumab, ARRY380, the combination thereof, and a biparatopic, HER2-targeted designed ankyrin repeat protein (DARPin; specifically, 6L1G) and quantified the phosphoproteome by isobaric tagging using tandem mass tag liquid chromatography/tandem mass spectrometry (TMT LC-MS/MS). We found a specific signature of persistently phosphorylated tyrosine peptides after the nonapoptotic treatments, which we used to distinguish between different treatment-induced cancer cell fates. Next, we analyzed the activation of serine/threonine and tyrosine kinases after treatment using a bait peptide chip array and predicted the corresponding active kinases. Through a combined system-wide analysis, we identified a common adaptive kinase response program that involved the activation of focal adhesion kinase 1 (FAK1), protein kinase C-δ (PRKCD), and Ephrin (EPH) family receptors. These findings reveal potential targets to prevent adaptive resistance to HER2-targeted therapies.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Quinasas / Neoplasias de la Mama / Transducción de Señal / Receptor ErbB-2 / Bibliotecas de Moléculas Pequeñas / Trastuzumab Tipo de estudio: Prognostic_studies Límite: Female / Humans Idioma: En Revista: Sci Signal Asunto de la revista: CIENCIA / FISIOLOGIA Año: 2019 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Quinasas / Neoplasias de la Mama / Transducción de Señal / Receptor ErbB-2 / Bibliotecas de Moléculas Pequeñas / Trastuzumab Tipo de estudio: Prognostic_studies Límite: Female / Humans Idioma: En Revista: Sci Signal Asunto de la revista: CIENCIA / FISIOLOGIA Año: 2019 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Estados Unidos