title: Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer.
abstract: 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.
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Lovly
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Nerina T
authors.initials: NT
authors.lastname: McDonald
authors.affiliation: Department of Biostatistics, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Heidi
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Translational Genomics, Center of Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Ortiz-Cuaran
authors.affiliation: 1] Department of Pathology, Center for Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany. [2] New Oncology, Cologne, Germany.
authors.forename: Lukas C
authors.initials: LC
authors.lastname: Heukamp
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Yingjun
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Pathology, Center for Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Florin
authors.affiliation: Department of Pathology, Center for Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany.
authors.forename: Luka
authors.initials: L
authors.lastname: Ozretić
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Lim
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Biostatistics, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Biostatistics, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Lu
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Paul K
authors.initials: PK
authors.lastname: Paik
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Ronglai
authors.initials: R
authors.lastname: Shen
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Hailing
authors.initials: H
authors.lastname: Jin
authors.affiliation: Department of Pathology, Center for Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Buettner
authors.affiliation: Department of Internal Medicine (Department I), Center for Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Ansén
authors.affiliation: Department of Prostate Cancer Research, Institute of Pathology, Center of Integrated Oncology Köln-Bonn, University Hospital of Bonn, Bonn, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Perner
authors.affiliation: Department of Pathology, Hospital Merheim, Cologne, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Brockmann
authors.affiliation: 1] Department of Translational Genomics, Center of Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany. [2] Department of Internal Medicine (Department I), Center for Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Bos
authors.affiliation: Department of Internal Medicine (Department I), Center for Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wolf
authors.affiliation: Department of Internal Medicine (Department I), Center for Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany.
authors.forename: Masyar
authors.initials: M
authors.lastname: Gardizi
authors.affiliation: Department of Surgery, University of Melbourne, St. Vincent's Hospital, Melbourne, Victoria, Australia.
authors.forename: Gavin M
authors.initials: GM
authors.lastname: Wright
authors.affiliation: Division of Hematology and Medical Oncology, Peter MacCallum Cancer Center, Melbourne, Australia.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Solomon
authors.affiliation: Department of Anatomical Pathology, St. Vincent's Hospital, Melbourne, Victoria, Australia.
authors.forename: Prudence A
authors.initials: PA
authors.lastname: Russell
authors.affiliation: Department of Pathology, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.
authors.forename: Toni-Maree
authors.initials: TM
authors.lastname: Rogers
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Suehara
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Red-Brewer
authors.affiliation: Anti-tumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Rudy
authors.initials: R
authors.lastname: Tieu
authors.affiliation: Anti-tumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Elisa
authors.initials: E
authors.lastname: de Stanchina
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Qingguo
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Zhongming
authors.identifier: 0000000234770914
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Medicine, UT Southwestern School of Medicine, Dallas, Texas, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Johnson
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Leora
authors.initials: L
authors.lastname: Horn
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.affiliation: 1] Department of Translational Genomics, Center of Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany. [2] Department of Pathology, Center for Integrated Oncology Köln-Bonn, University Hospital Cologne, Cologne, Germany.
authors.forename: Roman K
authors.initials: RK
authors.lastname: Thomas
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: William
authors.initials: W
authors.lastname: Pao
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000077547:Crizotinib; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D008875:Middle Aged; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000187:drug effects*; D017526:Receptor, IGF Type 1 / Q000187:drug effects* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1