title: Lapatinib Resistance in Breast Cancer Cells Is Accompanied by Phosphorylation-Mediated Reprogramming of Glycolysis.
abstract: HER2/ERBB2-overexpressing breast cancers targeted effectively by the small-molecule kinase inhibitor lapatinib frequently acquire resistance to this drug. In this study, we employed explorative mass spectrometry to profile proteome, kinome, and phosphoproteome changes in an established model of lapatinib resistance to systematically investigate initial inhibitor response and subsequent reprogramming in resistance. The resulting dataset, which collectively contains quantitative data for >7,800 proteins, >300 protein kinases, and >15,000 phosphopeptides, enabled deep insight into signaling recovery and molecular reprogramming upon resistance. Our data-driven approach confirmed previously described mechanisms of resistance (e.g., AXL overexpression and PIK3 reactivation), revealed novel pharmacologically actionable targets, and confirmed the expectation of significant heterogeneity in molecular resistance drivers inducing distinct phenotypic changes. Furthermore, our approach identified an extensive and exclusively phosphorylation-mediated reprogramming of glycolytic activity, supported additionally by widespread changes of corresponding metabolites and an increased sensitivity towards glycolysis inhibition. Collectively, our multi-omic analysis offers deeper perspectives on cancer drug resistance and suggests new biomarkers and treatment options for lapatinib-resistant cancers.Cancer Res; 77(8); 1842-53. ©2017 AACR.
authors.affiliation: Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany.|Center for Integrated Protein Science Munich (CIPSM), Freising, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ruprecht
authors.affiliation: Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.
authors.forename: Esther A
authors.initials: EA
authors.lastname: Zaal
authors.affiliation: Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Zecha
authors.affiliation: Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.affiliation: Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.
authors.forename: Celia R
authors.initials: CR
authors.lastname: Berkers
authors.affiliation: Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany. S.M.Lemeer@uu.nl kuster@tum.de.|Center for Integrated Protein Science Munich (CIPSM), Freising, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|Bavarian Biomolecular Mass Spectrometry Center, Technical University of Munich, Freising, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Kuster
authors.affiliation: Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany. S.M.Lemeer@uu.nl kuster@tum.de.|Center for Integrated Protein Science Munich (CIPSM), Freising, Germany.|Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.
authors.forename: Simone
authors.initials: S
authors.lastname: Lemeer
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D065150:Cellular Reprogramming / Q000502:physiology; D019008:Drug Resistance, Neoplasm; D005260:Female; D006019:Glycolysis; D006801:Humans; D000077341:Lapatinib; D010766:Phosphorylation; D040901:Proteomics / Q000379:methods; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human