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         headline:Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer
         description:Trever Bivona and colleagues identify the upregulation of the AXL kinase in human non–small cell lung cancer with acquired resistance to erlotinib. Inhibition of AXL restores sensitivity to erlotinib in in vitro and in vivo tumor models. The authors suggest AXL as a potential therapeutic target that may prevent or overcome acquired resistance in patients with EGFR-mutant lung cancer. Human non–small cell lung cancers (NSCLCs) with activating mutations in EGFR frequently respond to treatment with EGFR-targeted tyrosine kinase inhibitors (TKIs), such as erlotinib, but responses are not durable, as tumors acquire resistance. Secondary mutations in EGFR (such as T790M) or upregulation of the MET kinase are found in over 50% of resistant tumors. Here, we report increased activation of AXL and evidence for epithelial-to-mesenchymal transition (EMT) in multiple in vitro and in vivo EGFR-mutant lung cancer models with acquired resistance to erlotinib in the absence of the EGFR p.Thr790Met alteration or MET activation. Genetic or pharmacological inhibition of AXL restored sensitivity to erlotinib in these tumor models. Increased expression of AXL and, in some cases, of its ligand GAS6 was found in EGFR-mutant lung cancers obtained from individuals with acquired resistance to TKIs. These data identify AXL as a promising therapeutic target whose inhibition could prevent or overcome acquired resistance to EGFR TKIs in individuals with EGFR-mutant lung cancer.
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      headline:Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer
      description:Trever Bivona and colleagues identify the upregulation of the AXL kinase in human non–small cell lung cancer with acquired resistance to erlotinib. Inhibition of AXL restores sensitivity to erlotinib in in vitro and in vivo tumor models. The authors suggest AXL as a potential therapeutic target that may prevent or overcome acquired resistance in patients with EGFR-mutant lung cancer. Human non–small cell lung cancers (NSCLCs) with activating mutations in EGFR frequently respond to treatment with EGFR-targeted tyrosine kinase inhibitors (TKIs), such as erlotinib, but responses are not durable, as tumors acquire resistance. Secondary mutations in EGFR (such as T790M) or upregulation of the MET kinase are found in over 50% of resistant tumors. Here, we report increased activation of AXL and evidence for epithelial-to-mesenchymal transition (EMT) in multiple in vitro and in vivo EGFR-mutant lung cancer models with acquired resistance to erlotinib in the absence of the EGFR p.Thr790Met alteration or MET activation. Genetic or pharmacological inhibition of AXL restored sensitivity to erlotinib in these tumor models. Increased expression of AXL and, in some cases, of its ligand GAS6 was found in EGFR-mutant lung cancers obtained from individuals with acquired resistance to TKIs. These data identify AXL as a promising therapeutic target whose inhibition could prevent or overcome acquired resistance to EGFR TKIs in individuals with EGFR-mutant lung cancer.
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         Cancer genomics
         Cancer therapeutic resistance
         Gene therapy
         Non-small-cell lung cancer
         Biomedicine
         general
         Human Genetics
         Cancer Research
         Agriculture
         Gene Function
         Animal Genetics and Genomics
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               type:PostalAddress
            type:Organization
      name:Charles Sawyers
      affiliation:
            name:Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center
            address:
               name:Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, USA
               type:PostalAddress
            type:Organization
      name:Titus J Boggon
      affiliation:
            name:Yale University School of Medicine
            address:
               name:Department of Pharmacology, Yale University School of Medicine, New Haven, USA
               type:PostalAddress
            type:Organization
      name:Patrick C Ma
      affiliation:
            name:Aerodigestive Oncology Translational Research, Translational Hematology and Oncology Research (THOR), Cleveland Clinic Taussig Cancer Institute and Cleveland Clinic Lerner College of Medicine of Case Western Reserve University
            address:
               name:Aerodigestive Oncology Translational Research, Translational Hematology and Oncology Research (THOR), Cleveland Clinic Taussig Cancer Institute and Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, USA
               type:PostalAddress
            type:Organization
      name:Carlota Costa
      affiliation:
            name:Catalan Institute of Oncology, Hospital Germans Trias i Pujol
            address:
               name:Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Barcelona, Spain
               type:PostalAddress
            type:Organization
            name:Pangaea Biotech, USP Dexeus University Institute
            address:
               name:Pangaea Biotech, USP Dexeus University Institute, Barcelona, Spain
               type:PostalAddress
            type:Organization
      name:Miquel Taron
      affiliation:
            name:Catalan Institute of Oncology, Hospital Germans Trias i Pujol
            address:
               name:Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Barcelona, Spain
               type:PostalAddress
            type:Organization
            name:Pangaea Biotech, USP Dexeus University Institute
            address:
               name:Pangaea Biotech, USP Dexeus University Institute, Barcelona, Spain
               type:PostalAddress
            type:Organization
      name:Rafael Rosell
      affiliation:
            name:Catalan Institute of Oncology, Hospital Germans Trias i Pujol
            address:
               name:Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Barcelona, Spain
               type:PostalAddress
            type:Organization
            name:Pangaea Biotech, USP Dexeus University Institute
            address:
               name:Pangaea Biotech, USP Dexeus University Institute, Barcelona, Spain
               type:PostalAddress
            type:Organization
      name:Balazs Halmos
      affiliation:
            name:Columbia University Medical Center
            address:
               name:Division of Hematology/Oncology, Columbia University Medical Center, New York, USA
               type:PostalAddress
            type:Organization
      email:[email protected]
      name:Trever G Bivona
      affiliation:
            name:Helen Diller Comprehensive Cancer Center, University of California
            address:
               name:Division of Hematology/Oncology, Helen Diller Comprehensive Cancer Center, University of California, San Francisco, USA
               type:PostalAddress
            type:Organization
            name:Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center
            address:
               name:Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, USA
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Department of Pathology, Case Western Reserve University School of Medicine, University Hospitals–Case Medical Center and Ireland Cancer Center, Case Comprehensive Cancer Center, Cleveland, USA
      name:Division of Hematology/Oncology, Case Western Reserve University School of Medicine, University Hospitals–Case Medical Center and Ireland Cancer Center, Case Comprehensive Cancer Center, Cleveland, USA
      name:Division of Hematology/Oncology, Columbia University Medical Center, New York, USA
      name:Department of Oncology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea
      name:Division of Hematology/Oncology, Helen Diller Comprehensive Cancer Center, University of California, San Francisco, USA
      name:Division of Hematology/Oncology, Helen Diller Comprehensive Cancer Center, University of California, San Francisco, USA
      name:Division of Hematology/Oncology, Columbia University Medical Center, New York, USA
      name:Department of Genetics, Case Western Reserve University School of Medicine, University Hospitals–Case Medical Center and Ireland Cancer Center, Case Comprehensive Cancer Center, Cleveland, USA
      name:Division of Hematology/Oncology, Case Western Reserve University School of Medicine, University Hospitals–Case Medical Center and Ireland Cancer Center, Case Comprehensive Cancer Center, Cleveland, USA
      name:Division of Hematology/Oncology, Columbia University Medical Center, New York, USA
      name:Department of Pathology, Case Western Reserve University School of Medicine, University Hospitals–Case Medical Center and Ireland Cancer Center, Case Comprehensive Cancer Center, Cleveland, USA
      name:Division of Gastroenterology and Liver Disease, Case Western Reserve University School of Medicine, University Hospitals–Case Medical Center and Ireland Cancer Center, Case Comprehensive Cancer Center, Cleveland, USA
      name:Department of Pulmonary and Critical Care Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea
      name:Department of Pulmonary and Critical Care Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea
      name:Department of Oncology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea
      name:Department of Pulmonary and Critical Care Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea
      name:Department of Oncology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea
      name:Department of Pathology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea
      name:Department of Pathology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea
      name:Department of Pulmonary and Critical Care Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea
      name:Department of Oncology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea
      name:Department of Oncology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea
      name:Thoracic Medical Oncology, Memorial Sloan-Kettering Cancer Center, New York, USA
      name:Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, USA
      name:Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, USA
      name:Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, USA
      name:Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, USA
      name:Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, USA
      name:Department of Pharmacology, Yale University School of Medicine, New Haven, USA
      name:Aerodigestive Oncology Translational Research, Translational Hematology and Oncology Research (THOR), Cleveland Clinic Taussig Cancer Institute and Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, USA
      name:Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Barcelona, Spain
      name:Pangaea Biotech, USP Dexeus University Institute, Barcelona, Spain
      name:Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Barcelona, Spain
      name:Pangaea Biotech, USP Dexeus University Institute, Barcelona, Spain
      name:Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Barcelona, Spain
      name:Pangaea Biotech, USP Dexeus University Institute, Barcelona, Spain
      name:Division of Hematology/Oncology, Columbia University Medical Center, New York, USA
      name:Division of Hematology/Oncology, Helen Diller Comprehensive Cancer Center, University of California, San Francisco, USA
      name:Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, USA
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