title: Targeting the insulin-like growth factor receptor and Src signaling network for the treatment of non-small cell lung cancer.
abstract: BACKGROUND
  Therapeutic interventions in the insulin-like growth factor receptor (IGF-1R) pathway were expected to provide clinical benefits; however, IGF-1R tyrosine kinase inhibitors (TKIs) have shown limited antitumor efficacy, and the mechanisms conveying resistance to these agents remain elusive.
  
  
  METHODS
  The expression and activation of the IGF-1R and Src were assessed via the analysis of a publicly available dataset, as well as immunohistochemistry, Western blotting, RT-PCR, and in vitro kinase assays. The efficacy of IGF-1R TKIs alone or in combination with Src inhibitors was analyzed using MTT assays, colony formation assays, flow cytometric analysis, and xenograft tumor models.
  
  
  RESULTS
  The co-activation of IGF-1R and Src was observed in multiple human NSCLC cell lines as well as in a tissue microarray (n = 353). The IGF-1R and Src proteins mutually phosphorylate on their autophosphorylation sites. In high-pSrc-expressing NSCLC cells, linsitinib treatment initially inactivated the IGF-1R pathway but led a Src-dependent reactivation of downstream effectors. In low-pSrc-expressing NSCLC cells, linsitinib treatment decreased the turnover of the IGF-1R and Src proteins, ultimately amplifying the reciprocal co-activation of IGF-1R and Src. Co-targeting IGF-1R and Src significantly suppressed the proliferation and tumor growth of both high-pSrc-expressing and low-pSrc-expressing NSCLC cells in vitro and in vivo and the growth of patient-derived tissues in vivo.
  
  
  CONCLUSIONS
  Reciprocal activation between Src and IGF-1R occurs in NSCLC. Src causes IGF-1R TKI resistance by acting as a key downstream modulator of the cross-talk between multiple membrane receptors. Targeting Src is a clinically applicable strategy to overcome resistance to IGF-1R TKIs.
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 151-742, Republic of Korea. snoopy77@snu.ac.kr.
authors.forename: Hye-Young
authors.initials: HY
authors.lastname: Min
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 151-742, Republic of Korea. yunhj4476@hanmail.net.
authors.forename: Hye Jeong
authors.initials: HJ
authors.lastname: Yun
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 151-742, Republic of Korea. jslee5995@snu.ac.kr.
authors.forename: Ji-Sun
authors.initials: JS
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Inje University, Gimhae, Gyungnam, 621-749, Republic of Korea. hjlee@inje.ac.kr.
authors.forename: Hyo-Jong
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 151-742, Republic of Korea. gslife99@gmail.com.
authors.forename: Jaebeom
authors.initials: J
authors.lastname: Cho
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 151-742, Republic of Korea. violet558@nate.com.
authors.forename: Hyun-Ji
authors.initials: HJ
authors.lastname: Jang
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 151-742, Republic of Korea. psyji043@hanmail.net.
authors.forename: Shin-Hyung
authors.initials: SH
authors.lastname: Park
authors.affiliation: Department of Biostatistics, The University of Texas M. D. Anderson Cancer Cener, Houston, TX, USA. dianeliu@mdanderson.org.
authors.forename: Diane
authors.initials: D
authors.lastname: Liu
authors.affiliation: College of Pharmacy, Gachon University, Incheon, 406-840, Republic of Korea. shoh@gachon.ac.kr.
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Oh
authors.affiliation: Department of Biostatistics, The University of Texas M. D. Anderson Cancer Cener, Houston, TX, USA. jjlee@mdanderson.org.
authors.forename: J Jack
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Department of Thoracic/Head & Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Cener, Houston, TX, USA. iiwistuba@mdanderson.org.|Department of Pathology, The University of Texas M. D. Anderson Cancer Cener, Houston, TX, USA. iiwistuba@mdanderson.org.
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 151-742, Republic of Korea. hylee135@snu.ac.kr.
authors.forename: Ho-Young
authors.initials: HY
authors.lastname: Lee
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D058990:Molecular Targeted Therapy; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D055550:Protein Stability / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: C551528:3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D017526:Receptor, IGF Type 1; D019061:src-Family Kinases