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• ALK fusions in the pan-cancer setting: another tumor-agnostic target?

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      headline:Rationale for co-targeting IGF-1R and ALK in ALK fusion–positive lung cancer
      description:Activation of the insulin-like growth factor 1 receptor may underlie clinical resistance to inhibition of the anaplastic lymphoma receptor kinase in lung cancer. Crizotinib, a selective tyrosine kinase inhibitor (TKI), shows marked activity in patients whose lung cancers harbor fusions in the gene encoding anaplastic lymphoma receptor tyrosine kinase (ALK), but its efficacy is limited by variable primary responses and acquired resistance. In work arising from the clinical observation of a patient with ALK fusion–positive lung cancer who had an exceptional response to an insulin-like growth factor 1 receptor (IGF-1R)-specific antibody, we define a therapeutic synergism between ALK and IGF-1R inhibitors. Similar to IGF-1R, ALK fusion proteins bind to the adaptor insulin receptor substrate 1 (IRS-1), and IRS-1 knockdown enhances the antitumor effects of ALK inhibitors. In models of ALK TKI resistance, the IGF-1R pathway is activated, and combined ALK and IGF-1R inhibition improves therapeutic efficacy. Consistent with this finding, the levels of IGF-1R and IRS-1 are increased in biopsy samples from patients progressing on crizotinib monotherapy. Collectively these data support a role for the IGF-1R–IRS-1 pathway in both ALK TKI–sensitive and ALK TKI–resistant states and provide a biological rationale for further clinical development of dual ALK and IGF-1R inhibitors.
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            name:Memorial Sloan Kettering Cancer Center
            address:
               name:Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA
               type:PostalAddress
            type:Organization
      name:Monica Red-Brewer
      affiliation:
            name:Vanderbilt University
            address:
               name:Department of Medicine, Vanderbilt University, Nashville, USA
               type:PostalAddress
            type:Organization
      name:Rudy Tieu
      affiliation:
            name:Anti-tumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center
            address:
               name:Anti-tumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, USA
               type:PostalAddress
            type:Organization
      name:Elisa de Stanchina
      affiliation:
            name:Anti-tumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center
            address:
               name:Anti-tumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, USA
               type:PostalAddress
            type:Organization
      name:Qingguo Wang
      affiliation:
            name:Vanderbilt University
            address:
               name:Department of Biomedical Informatics, Vanderbilt University, Nashville, USA
               type:PostalAddress
            type:Organization
      name:Zhongming Zhao
      url:http://orcid.org/0000-0002-3477-0914
      affiliation:
            name:Vanderbilt University
            address:
               name:Department of Biomedical Informatics, Vanderbilt University, Nashville, USA
               type:PostalAddress
            type:Organization
      name:David H Johnson
      affiliation:
            name:UT Southwestern School of Medicine
            address:
               name:Department of Medicine, UT Southwestern School of Medicine, Dallas, USA
               type:PostalAddress
            type:Organization
      name:Leora Horn
      affiliation:
            name:Vanderbilt University
            address:
               name:Department of Medicine, Vanderbilt University, Nashville, USA
               type:PostalAddress
            type:Organization
      name:Kwok-Kin Wong
      affiliation:
            name:Dana-Farber Cancer Institute
            address:
               name:Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA
               type:PostalAddress
            type:Organization
      name:Roman K Thomas
      affiliation:
            name:Center of Integrated Oncology Köln-Bonn, University Hospital Cologne
            address:
               name:Department of Translational Genomics, Center of Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
            name:Center for Integrated Oncology Köln-Bonn, University Hospital Cologne
            address:
               name:Department of Pathology, Center for Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany
               type:PostalAddress
            type:Organization
      name:Marc Ladanyi
      affiliation:
            name:Memorial Sloan Kettering Cancer Center
            address:
               name:Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA
               type:PostalAddress
            type:Organization
      name:William Pao
      affiliation:
            name:Vanderbilt University
            address:
               name:Department of Medicine, Vanderbilt University, Nashville, USA
               type:PostalAddress
            type:Organization
PostalAddress:
      name:Department of Medicine, Vanderbilt University, Nashville, USA
      name:Department of Medicine, Vanderbilt University, Nashville, USA
      name:Department of Biostatistics, Vanderbilt University, Nashville, USA
      name:Department of Translational Genomics, Center of Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany
      name:Department of Pathology, Center for Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany
      name:New Oncology, Cologne, Germany
      name:Department of Medicine, Vanderbilt University, Nashville, USA
      name:Department of Pathology, Center for Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany
      name:Department of Pathology, Center for Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany
      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:Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA
      name:Department of Biostatistics, Vanderbilt University, Nashville, USA
      name:Department of Biostatistics, Vanderbilt University, Nashville, USA
      name:Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA
      name:Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, USA
      name:Department of Medicine, Vanderbilt University, Nashville, USA
      name:Department of Pathology, Center for Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany
      name:Department of Internal Medicine (Department I), Center for Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany
      name:Department of Prostate Cancer Research, Institute of Pathology, Center of Integrated Oncology Köln-Bonn, University Hospital of Bonn, Bonn, Germany
      name:Department of Pathology, Hospital Merheim, Cologne, Germany
      name:Department of Translational Genomics, Center of Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany
      name:Department of Internal Medicine (Department I), Center for Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany
      name:Department of Internal Medicine (Department I), Center for Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany
      name:Department of Internal Medicine (Department I), Center for Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany
      name:Department of Surgery, University of Melbourne, St. Vincent's Hospital, Melbourne, Australia
      name:Division of Hematology and Medical Oncology, Peter MacCallum Cancer Center, Melbourne, Australia
      name:Department of Anatomical Pathology, St. Vincent's Hospital, Melbourne, Australia
      name:Department of Pathology, Peter MacCallum Cancer Center, Melbourne, Australia
      name:Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA
      name:Department of Medicine, Vanderbilt University, Nashville, USA
      name:Anti-tumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, USA
      name:Anti-tumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, USA
      name:Department of Biomedical Informatics, Vanderbilt University, Nashville, USA
      name:Department of Biomedical Informatics, Vanderbilt University, Nashville, USA
      name:Department of Medicine, UT Southwestern School of Medicine, Dallas, USA
      name:Department of Medicine, Vanderbilt University, Nashville, USA
      name:Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA
      name:Department of Translational Genomics, Center of Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany
      name:Department of Pathology, Center for Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany
      name:Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA
      name:Department of Medicine, Vanderbilt University, Nashville, USA
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