title: Inhibition of IGF1R signaling abrogates resistance to afatinib (BIBW2992) in EGFR T790M mutant lung cancer cells.
abstract: Non-small cell lung cancer (NSCLC) patients with an epidermal growth factor receptor (EGFR) mutation have benefited from treatment of reversible EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib. Acquisition of a secondary mutation in EGFR T790M is the most common mechanism of resistance to first generation EGFR TKIs, resulting in therapeutic failure. Afatinib is a second generation of EGFR TKI that showed great efficacy against tumors bearing the EGFR T790M mutation, but it failed to show the improvement on overall survival of lung cancer patients with EGFR mutations possibly because of novel acquired resistance mechanisms. Currently, there are no therapeutic options available for lung cancer patients who develop acquired resistance to afatinib. To identify novel resistance mechanism(s) to afatinib, we developed afatinib resistant cell lines from a parental human-derived NSCLC cell line, H1975, harboring both EGFR L858R and T790M mutations. We found that activation of the insulin-like growth factor 1 receptor (IGF1R) signaling pathway contributes to afatinib resistance in NSCLC cells harboring the T790M mutation. IGF1R knockdown not only significantly sensitizes resistant cells to afatinib, but also induces apoptosis in afatinib resistance cells. In addition, combination treatment with afatinib and linsitinib shows more than additive effects on tumor growth in in vivo H1975 xenograft. Therefore, these finding suggest that IGF1R inhibition or combination of EGFR-IGF1R inhibition strategies would be potential ways to prevent or potentiate the effects of current therapeutic options to lung cancer patients demonstrating resistance to either first or second generation EGFR TKIs.
authors.affiliation: Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Yongik
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Yian
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Michael
authors.initials: M
authors.lastname: James
authors.affiliation: Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Jeong
authors.affiliation: Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin.|Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Ming
authors.initials: M
authors.lastname: You
mesh_terms: D000077716:Afatinib; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D066246:ErbB Receptors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D051379:Mice; D009154:Mutation; D011719:Pyrazines / Q000008:administration & dosage* / Q000494:pharmacology; D011799:Quinazolines / Q000008:administration & dosage / Q000627:therapeutic use; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C551528:3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol; C000597236:IGF1R protein, human; D007093:Imidazoles; D011719:Pyrazines; D011799:Quinazolines; D017451:Receptors, Somatomedin; D000077716:Afatinib; C512478:EGFR protein, human; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1
keywords: EGFR; IGF1R; afatinib; cellular response to anticancer drugs; lung cancer; reversal of drug resistance