title: IGFBP2/FAK pathway is causally associated with dasatinib resistance in non-small cell lung cancer cells.
abstract: Insulin-like growth factor (IGF)-binding protein-2 (IGFBP2) expression is increased in various types of cancers, including in a subset of patients with lung cancer. Because IGFBP2 is involved in signal transduction of some critical cancer-related pathways, we analyzed the association between IGFBP2 and response to pathway-targeted agents in seven human non-small cell lung cancer (NSCLC) cell lines. Western blot analysis and ELISA showed that four of the seven NSCLC cell lines analyzed expressed high levels of IGFBP2, whereas the remaining three had barely detectable IGFBP2. Susceptibilities of those seven cell lines to nine anticancer agents targeting to IGF1R, Src, FAK, MEK, and AKT were determined by a dose-dependent cell viability assay. The results showed that high IGFBP2 levels were associated with resistance to dasatinib and, to a lesser degree, to sacaratinib, but not to other agents. Ectopic IGFBP2 overexpression or knockdown revealed that changing IGFBP2 expression levels reversed dasatinib susceptibility phenotype, suggesting a causal relationship between IGFBP2 expression and dasatinib resistance. Molecular characterization revealed that focal adhesion kinase (FAK) activation was associated with increased IGFBP2 expression and partially contributed to IGFBP2-mediated dasatinib resistance. Treatment with a combination of dasatinib and FAK inhibitor led to enhanced antitumor activity in IGFBP2-overexpressing and dasatinib-resistant NSCLC cells in vitro and in vivo. Our results showed that the IGFBP2/FAK pathway is causally associated with dasatinib resistance and may be used as biomarkers for identification of dasatinib responders among patients with lung cancer. Simultaneous targeting on Src and FAK will likely improve the therapeutic efficacy of dasatinib for treatment of lung cancer.
authors.affiliation: Corresponding Author: Bingliang Fang, Department of Thoracic and Cardiovascular Surgery, Unit 445, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. bfang@mdanderson.org.
authors.forename: Haibo
authors.initials: H
authors.lastname: Lu
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Wen
authors.initials: W
authors.lastname: Gao
authors.forename: Jieru
authors.initials: J
authors.lastname: Meng
authors.forename: Bingbing
authors.initials: B
authors.lastname: Dai
authors.forename: Shuhong
authors.initials: S
authors.lastname: Wu
authors.forename: John
authors.initials: J
authors.lastname: Minna
authors.forename: Jack A
authors.initials: JA
authors.lastname: Roth
authors.forename: Wayne L
authors.initials: WL
authors.lastname: Hofstetter
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Swisher
authors.forename: Bingliang
authors.initials: B
authors.lastname: Fang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D052117:Benzodioxoles / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D000069439:Dasatinib; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004789:Enzyme Activation; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D020128:Inhibitory Concentration 50; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D052117:Benzodioxoles; D018971:Insulin-Like Growth Factor Binding Protein 2; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; D013844:Thiazoles; C515233:saracatinib; D051416:Focal Adhesion Protein-Tyrosine Kinases; D000069439:Dasatinib