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GATA3 and MDM2 are synthetic lethal in estrogen receptor-positive breast cancers.
Bianco, Gaia; Coto-Llerena, Mairene; Gallon, John; Kancherla, Venkatesh; Taha-Mehlitz, Stephanie; Marinucci, Mattia; Konantz, Martina; Srivatsa, Sumana; Montazeri, Hesam; Panebianco, Federica; Tirunagaru, Vijaya G; De Menna, Marta; Paradiso, Viola; Ercan, Caner; Dahmani, Ahmed; Montaudon, Elodie; Beerenwinkel, Niko; Kruithof-de Julio, Marianna; Terracciano, Luigi M; Lengerke, Claudia; Jeselsohn, Rinath M; Doebele, Robert C; Bidard, François-Clément; Marangoni, Elisabetta; Ng, Charlotte K Y; Piscuoglio, Salvatore.
Afiliação
  • Bianco G; Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland.
  • Coto-Llerena M; Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland.
  • Gallon J; Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
  • Kancherla V; Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland.
  • Taha-Mehlitz S; Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
  • Marinucci M; Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland.
  • Konantz M; Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland.
  • Srivatsa S; Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland.
  • Montazeri H; Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.
  • Panebianco F; Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
  • Tirunagaru VG; Department of Bioinformatics, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
  • De Menna M; Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland.
  • Paradiso V; Rain Therapeutics Inc, Newark, CA, USA.
  • Ercan C; Department of Biomedical Research, Urology Group, University of Bern, Bern, Switzerland.
  • Dahmani A; Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland.
  • Montaudon E; Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
  • Beerenwinkel N; Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
  • Kruithof-de Julio M; Laboratory of Preclinical Investigation, Department of Translational Research, Institut Curie Research Center, Paris, France.
  • Terracciano LM; Laboratory of Preclinical Investigation, Department of Translational Research, Institut Curie Research Center, Paris, France.
  • Lengerke C; Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.
  • Jeselsohn RM; Department of Biomedical Research, Urology Group, University of Bern, Bern, Switzerland.
  • Doebele RC; Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
  • Bidard FC; Department of Pathology, Humanitas Clinical and Research Center, IRCCS, Milan, Italy.
  • Marangoni E; Department of Biomedical Sciences, Humanitas University, Milan, Italy.
  • Ng CKY; Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland.
  • Piscuoglio S; Division of Women's Cancers, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Commun Biol ; 5(1): 373, 2022 04 19.
Article em En | MEDLINE | ID: mdl-35440675
ABSTRACT
Synthetic lethal interactions, where the simultaneous but not individual inactivation of two genes is lethal to the cell, have been successfully exploited to treat cancer. GATA3 is frequently mutated in estrogen receptor (ER)-positive breast cancers and its deficiency defines a subset of patients with poor response to hormonal therapy and poor prognosis. However, GATA3 is not yet targetable. Here we show that GATA3 and MDM2 are synthetically lethal in ER-positive breast cancer. Depletion and pharmacological inhibition of MDM2 significantly impaired tumor growth in GATA3-deficient models in vitro, in vivo and in patient-derived organoids/xenograft (PDOs/PDX) harboring GATA3 somatic mutations. The synthetic lethality requires p53 and acts via the PI3K/Akt/mTOR pathway. Our results present MDM2 as a therapeutic target in the substantial cohort of ER-positive, GATA3-mutant breast cancer patients. With MDM2 inhibitors widely available, our findings can be rapidly translated into clinical trials to evaluate in-patient efficacy.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Antineoplásicos Idioma: En Ano de publicação: 2022 Tipo de documento: Article
Texto completo
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XML
PubMed Links
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Antineoplásicos Idioma: En Ano de publicação: 2022 Tipo de documento: Article