title: FGFR1 activation is an escape mechanism in human lung cancer cells resistant to afatinib, a pan-EGFR family kinase inhibitor.
abstract: Most NSCLC patients with EGFR mutations benefit from treatment with EGFR-TKIs, but the clinical efficacy of EGFR-TKIs is limited by the appearance of drug resistance. Multiple kinase inhibitors of EGFR family proteins such as afatinib have been newly developed to overcome such drug resistance. We established afatinib-resistant cell lines after chronic exposure of activating EGFR mutation-positive PC9 cells to afatinib. Afatinib-resistant cells showed following specific characteristics as compared to PC9: [1] Expression of EGFR family proteins and their phosphorylated molecules was markedly downregulated by selection of afatinib resistance; [2] Expression of FGFR1 and its ligand FGF2 was alternatively upregulated; [3] Treatment with anti-FGF2 neutralizing antibody blocked enhanced phosphorylation of FGFR in resistant clone; [4] Both resistant clones showed collateral sensitivity to PD173074, a small-molecule FGFR-TKIs, and treatment with either PD173074 or FGFR siRNA exacerbated suppression of both afatinib-resistant Akt and Erk phosphorylation when combined with afatinib; [5] Expression of twist was markedly augmented in resistant sublines, and twist knockdown specifically suppressed FGFR expression and cell survival. Together, enhanced expression of FGFR1 and FGF2 thus plays as an escape mechanism for cell survival of afatinib-resistant cancer cells, that may compensate the loss of EGFR-driven signaling pathway.
authors.affiliation: Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan;
authors.forename: Koichi
authors.initials: K
authors.lastname: Azuma
authors.affiliation: Department of Diagnostic Pathology, Kurume University Hospital, Kurume, Fukuoka, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kawahara
authors.affiliation: Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kahori
authors.initials: K
authors.lastname: Sonoda
authors.affiliation: Department of Diagnostic Pathology, Kurume University Hospital, Kurume, Fukuoka, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Nakashima
authors.affiliation: Department of Bioscience and Biotechnology, Kyushu University, Fukuoka, Japan.
authors.forename: Kousuke
authors.initials: K
authors.lastname: Tashiro
authors.affiliation: Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Watari
authors.affiliation: Department of Occupational Pneumology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Izumi
authors.affiliation: Department of Diagnostic Pathology, Kurume University Hospital, Kurume, Fukuoka, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Kage
authors.affiliation: Laboratory of Molecular Cancer Biology, Department of Clinical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Michihiko
authors.initials: M
authors.lastname: Kuwano
authors.affiliation: Department of Pharmaceutical Oncology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ono
authors.affiliation: Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Hoshino
mesh_terms: D000077716:Afatinib; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D000077716:Afatinib; C512478:EGFR protein, human; D066246:ErbB Receptors; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051058:Oncogene Protein v-akt