title: Loss of ARID1A Activates ANXA1, which Serves as a Predictive Biomarker for Trastuzumab Resistance.
abstract: OBJECTIVE
  Despite the substantial progress in the development of targeted anticancer drugs, treatment failure due to primary or acquired resistance is still a major hurdle in the effective treatment of most advanced human cancers. Understanding these resistance mechanisms will be instrumental to improve personalized cancer treatment.
  
  
  METHODS
  Genome-wide loss-of-function genetic screens were performed to identify genes implicated in resistance to HER2/PI3K/mTOR targeting agents in HER2+breast cancer cell lines. Expression and adjuvant trastuzumab response data from the HER2+breast cancer trials FinHer and Responsify were used to validate our findings in patient series.
  
  
  RESULTS
  We find that reduced ARID1A expression confers resistance to several drugs that inhibit the HER2/PI3K/mTOR signaling cascade at different levels. We demonstrate that ARID1A loss activates annexin A1 (ANXA1) expression, which is required for drug resistance through its activation of AKT. We find that the AKT inhibitor MK2206 restores sensitivity of ARID1A knockdown breast cancer cells to both the mTOR kinase inhibitor AZD8055 and trastuzumab. Consistent with these in vitro data, we find in two independent HER2+breast cancer patient series that high ANXA1 expression is associated with resistance to adjuvant trastuzumab-based therapy.
  
  
  CONCLUSIONS
  Our findings provide a rationale for why tumors accumulate ARID1A mutations and identify high ANXA1 expression as a predictive biomarker for trastuzumab-based treatment. Our findings also suggest strategies to treat breast cancers with elevated ANXA1 expression. Clin Cancer Res; 22(21); 5238-48. ©2016 AACR.
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Katrien
authors.initials: K
authors.lastname: Berns
authors.affiliation: Translational Breast Cancer Laboratory, Free University of Brussels, Institute Jules Bordet, Brussels, Belgium.
authors.forename: Amir
authors.initials: A
authors.lastname: Sonnenblick
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Annemiek
authors.initials: A
authors.lastname: Gennissen
authors.affiliation: Translational Breast Cancer Laboratory, Free University of Brussels, Institute Jules Bordet, Brussels, Belgium.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Brohée
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: E Marielle
authors.initials: EM
authors.lastname: Hijmans
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Bastiaan
authors.initials: B
authors.lastname: Evers
authors.affiliation: Translational Breast Cancer Laboratory, Free University of Brussels, Institute Jules Bordet, Brussels, Belgium.
authors.forename: Debora
authors.initials: D
authors.lastname: Fumagalli
authors.affiliation: Translational Breast Cancer Laboratory, Free University of Brussels, Institute Jules Bordet, Brussels, Belgium.
authors.forename: Christine
authors.initials: C
authors.lastname: Desmedt
authors.affiliation: GBG German Breast Group, Neu Isenburg, Germany.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Loibl
authors.affiliation: Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Denkert
authors.affiliation: Multidisciplinary Breast Center, KU Leuven, University Hospitals, Leuven, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Neven
authors.affiliation: Department of Systems Biology, The University of Texas, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.affiliation: Department of Systems Biology, The University of Texas, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Theo A
authors.initials: TA
authors.lastname: Knijnenburg
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Tjalling
authors.initials: T
authors.lastname: Bosse
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Michiel S
authors.initials: MS
authors.lastname: van der Heijden
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Sanne
authors.initials: S
authors.lastname: Hindriksen
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Wouter
authors.initials: W
authors.lastname: Nijkamp
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Lodewyk F A
authors.initials: LF
authors.lastname: Wessels
authors.affiliation: Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Joensuu
authors.affiliation: Department of Systems Biology, The University of Texas, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Roderick L
authors.initials: RL
authors.lastname: Beijersbergen
authors.affiliation: Translational Breast Cancer Laboratory, Free University of Brussels, Institute Jules Bordet, Brussels, Belgium.
authors.forename: Christos
authors.initials: C
authors.lastname: Sotiriou
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands. r.bernards@nki.nl.
authors.forename: René
authors.initials: R
authors.lastname: Bernards
mesh_terms: D017305:Annexin A1 / Q000378:metabolism*; D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D061986:MCF-7 Cells; D009025:Morpholines / Q000494:pharmacology; D009687:Nuclear Proteins / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D000068878:Trastuzumab / Q000494:pharmacology*
chemical_list: D017305:Annexin A1; D000074322:Antineoplastic Agents, Immunological; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D006575:Heterocyclic Compounds, 3-Ring; D009025:Morpholines; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; D000068878:Trastuzumab; C112476:ARID1A protein, human; C548887:MK 2206; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol