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nature portfolio privacy policy thoracic oncology service research agreements advertising valuable tools scientific merit award universal nature 0/ reprints open label open-label constructs targeting gfp nature 462 nature 483 nature 376 nature 455 nature small-cell lung cancer small-cell lung cancer small-cell lung cancers small-cell lung cancers transit-lt1 transfection reagent tki-resistant cell lines egfr-mutant lung cancers egfr mutant-resistant cancers tyrosine kinase inhibitors nih/national cancer institute author correspondence patient-derived cell lines erlotinib-resistant cell lines alk-rearranged lung cancers paraffin-embedded tissue sections bonferroni post-hoc test celltiter-glo assay reagent full size image rb-deficient adenocarcinomas serves molecular details underlying tumour/cell line samples yield resistant cells/tumours removing low expressing cancer drug development exome-enriched gdna fragments advanced egfr mutation-positive cell lines established lose egfr expression cell viability assays alk kinase inhibitors small-cell carcinoma small-cell carcinoma squamous cell carcinoma

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         headline:RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer
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      headline:RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer
      description:Tyrosine kinase inhibitors are effective treatments for non-small-cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations. However, relapse typically occurs after an average of 1 year of continuous treatment. A fundamental histological transformation from NSCLC to small-cell lung cancer (SCLC) is observed in a subset of the resistant cancers, but the molecular changes associated with this transformation remain unknown. Analysis of tumour samples and cell lines derived from resistant EGFR mutant patients revealed that Retinoblastoma (RB) is lost in 100% of these SCLC transformed cases, but rarely in those that remain NSCLC. Further, increased neuroendocrine marker and decreased EGFR expression as well as greater sensitivity to BCL2 family inhibition are observed in resistant SCLC transformed cancers compared with resistant NSCLCs. Together, these findings suggest that this subset of resistant cancers ultimately adopt many of the molecular and phenotypic characteristics of classical SCLC. Resistance to tyrosine kinase inhibitors occurs in treatments of non-small-cell lung cancers (NSCLCs) with EGFR mutations but the mechanisms underlying this acquired resistance are unknown. Here the authors examine the molecular changes that occur in resistant cancers that transition from NSCLC to small-cell lung cancer phenotype and implicate loss of retinoblastoma in this process.
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            address:
               name:Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
               type:PostalAddress
            type:Organization
      name:Daniel B. Costa
      affiliation:
            name:Beth Israel Deaconess Medical Center, Harvard Medical School
            address:
               name:Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
               type:PostalAddress
            type:Organization
      name:Pasi A. Jänne
      affiliation:
            name:Belfer Institute of Applied Science, Dana Farber Cancer Institute
            address:
               name:Department of Medical Oncology, Belfer Institute of Applied Science, Dana Farber Cancer Institute, Boston, USA
               type:PostalAddress
            type:Organization
            name:Brigham and Women’s Hospital and Harvard Medical School
            address:
               name:Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA
               type:PostalAddress
            type:Organization
      name:Darrell R. Borger
      affiliation:
            name:Massachusetts General Hospital Cancer Center, Massachusetts General Hospital
            address:
               name:Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, USA
               type:PostalAddress
            type:Organization
            name:Harvard Medical School
            address:
               name:Department of Medicine, Harvard Medical School, Boston, USA
               type:PostalAddress
            type:Organization
      name:Sridhar Ramaswamy
      affiliation:
            name:Massachusetts General Hospital Cancer Center, Massachusetts General Hospital
            address:
               name:Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, USA
               type:PostalAddress
            type:Organization
            name:Harvard Medical School
            address:
               name:Department of Medicine, Harvard Medical School, Boston, USA
               type:PostalAddress
            type:Organization
            name:Broad Institute of MIT and Harvard, Cancer Genome Comparative Analysis Group
            address:
               name:Broad Institute of MIT and Harvard, Cancer Genome Comparative Analysis Group, Cambridge, USA
               type:PostalAddress
            type:Organization
      name:Toshi Shioda
      affiliation:
            name:Harvard Medical School
            address:
               name:Department of Medicine, Harvard Medical School, Boston, USA
               type:PostalAddress
            type:Organization
            name:Molecular Profiling Laboratory, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital
            address:
               name:Molecular Profiling Laboratory, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, USA
               type:PostalAddress
            type:Organization
      name:Anthony J. Iafrate
      affiliation:
            name:Massachusetts General Hospital Cancer Center
            address:
               name:Department of Pathology, Massachusetts General Hospital Cancer Center, Boston, USA
               type:PostalAddress
            type:Organization
            name:Harvard Medical School
            address:
               name:Department of Pathology, Harvard Medical School, Boston, USA
               type:PostalAddress
            type:Organization
      name:Gad Getz
      affiliation:
            name:Harvard Medical School
            address:
               name:Department of Medicine, Harvard Medical School, Boston, USA
               type:PostalAddress
            type:Organization
            name:Broad Institute of MIT and Harvard, Cancer Genome Comparative Analysis Group
            address:
               name:Broad Institute of MIT and Harvard, Cancer Genome Comparative Analysis Group, Cambridge, USA
               type:PostalAddress
            type:Organization
            name:Massachusetts General Hospital Cancer Center
            address:
               name:Department of Pathology, Massachusetts General Hospital Cancer Center, Boston, USA
               type:PostalAddress
            type:Organization
      name:Charles M. Rudin
      affiliation:
            name:Memorial Sloan Kettering Cancer Center, Thoracic Oncology Service
            address:
               name:Memorial Sloan Kettering Cancer Center, Thoracic Oncology Service, New York, USA
               type:PostalAddress
            type:Organization
      name:Mari Mino-Kenudson
      affiliation:
            name:Massachusetts General Hospital Cancer Center
            address:
               name:Department of Pathology, Massachusetts General Hospital Cancer Center, Boston, USA
               type:PostalAddress
            type:Organization
            name:Harvard Medical School
            address:
               name:Department of Pathology, Harvard Medical School, Boston, USA
               type:PostalAddress
            type:Organization
      name:Jeffrey A. Engelman
      affiliation:
            name:Massachusetts General Hospital Cancer Center, Massachusetts General Hospital
            address:
               name:Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, USA
               type:PostalAddress
            type:Organization
            name:Harvard Medical School
            address:
               name:Department of Medicine, Harvard Medical School, Boston, USA
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, USA
      name:Department of Medicine, Harvard Medical School, Boston, USA
      name:Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, USA
      name:Department of Medicine, Harvard Medical School, Boston, USA
      name:Memorial Sloan Kettering Cancer Center, Thoracic Oncology Service, New York, USA
      name:Broad Institute of MIT and Harvard, Cancer Genome Comparative Analysis Group, Cambridge, USA
      name:Department of Pathology, Massachusetts General Hospital Cancer Center, Boston, USA
      name:Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, USA
      name:Department of Medicine, Harvard Medical School, Boston, USA
      name:Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, USA
      name:Department of Medicine, Harvard Medical School, Boston, USA
      name:Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, USA
      name:Department of Medicine, Harvard Medical School, Boston, USA
      name:Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, USA
      name:Department of Medicine, Harvard Medical School, Boston, USA
      name:Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, USA
      name:Department of Medicine, Harvard Medical School, Boston, USA
      name:Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, USA
      name:Department of Medicine, Harvard Medical School, Boston, USA
      name:Present address: Catalan Institute of Oncology, Avinguda de la Granvia de l’Hospitalet, 199-203, 08907 Barcelona, Spain,
      name:Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, USA
      name:Department of Medicine, Harvard Medical School, Boston, USA
      name:Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, USA
      name:Department of Medicine, Harvard Medical School, Boston, USA
      name:Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, USA
      name:Department of Medicine, Harvard Medical School, Boston, USA
      name:Department of Pathology, Massachusetts General Hospital Cancer Center, Boston, USA
      name:Department of Pathology, Harvard Medical School, Boston, USA
      name:Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, USA
      name:Department of Medicine, Harvard Medical School, Boston, USA
      name:Department of Medicine, Harvard Medical School, Boston, USA
      name:Molecular Profiling Laboratory, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, USA
      name:Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
      name:Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
      name:Department of Medical Oncology, Belfer Institute of Applied Science, Dana Farber Cancer Institute, Boston, USA
      name:Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA
      name:Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, USA
      name:Department of Medicine, Harvard Medical School, Boston, USA
      name:Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, USA
      name:Department of Medicine, Harvard Medical School, Boston, USA
      name:Broad Institute of MIT and Harvard, Cancer Genome Comparative Analysis Group, Cambridge, USA
      name:Department of Medicine, Harvard Medical School, Boston, USA
      name:Molecular Profiling Laboratory, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, USA
      name:Department of Pathology, Massachusetts General Hospital Cancer Center, Boston, USA
      name:Department of Pathology, Harvard Medical School, Boston, USA
      name:Department of Medicine, Harvard Medical School, Boston, USA
      name:Broad Institute of MIT and Harvard, Cancer Genome Comparative Analysis Group, Cambridge, USA
      name:Department of Pathology, Massachusetts General Hospital Cancer Center, Boston, USA
      name:Memorial Sloan Kettering Cancer Center, Thoracic Oncology Service, New York, USA
      name:Department of Pathology, Massachusetts General Hospital Cancer Center, Boston, USA
      name:Department of Pathology, Harvard Medical School, Boston, USA
      name:Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, USA
      name:Department of Medicine, Harvard Medical School, Boston, USA

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