title: Hypoxia induces gefitinib resistance in non-small-cell lung cancer with both mutant and wild-type epidermal growth factor receptors.
abstract: Somatic mutations in the epidermal growth factor receptor (EGFR) gene, such as exon 19 deletion mutations, are important factors in determining therapeutic responses to gefitinib in non-small-cell lung cancer (NSCLC). However, some patients have activating mutations in EGFR and show poor responses to gefitinib. In this study, we examined three NSCLC cell lines, HCC827, PC9, and HCC2935, that expressed an EGFR exon 19 deletion mutation. All cells expressed mutant EGFR, but the PC9 and HCC2935 cells also expressed wild-type EGFR. The HCC827 cells were highly sensitive to gefitinib under both normoxia and hypoxia. However, the PC9 and HCC2935 cells were more resistant to gefitinib under hypoxic conditions compared to normoxia. Phosphorylation of EGFR and ERK was suppressed with gefitinib treatment to a lesser extent under hypoxia. The expression of transforming growth factor-α (TGFα) was dramatically upregulated under hypoxia, and the knockdown of TGFα or hypoxia-inducible factor-1α (HIF1α) reversed the resistance to gefitinib in hypoxic PC9 and HCC2935 cells. Finally, introduction of the wild-type EGFR gene into the HCC827 cells caused resistance to gefitinib under hypoxia. This phenomenon was also reversed by the knockdown of TGFα or HIF1α. Our results indicate that hypoxia causes gefitinib resistance in EGFR-mutant NSCLC through the activation of wild-type EGFR mediated by the upregulation of TGFα. The presence of wild-type and mutant EGFR along with tumor hypoxia are important factors that should be considered when treating NSCLC patients with gefitinib.
authors.affiliation: Department of Respiratory Medicine, Juntendo University, Tokyo, Japan.
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Minakata
authors.forename: Fumiyuki
authors.initials: F
authors.lastname: Takahashi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nara
authors.forename: Muneaki
authors.initials: M
authors.lastname: Hashimoto
authors.forename: Ken
authors.initials: K
authors.lastname: Tajima
authors.forename: Akiko
authors.initials: A
authors.lastname: Murakami
authors.forename: Fariz
authors.initials: F
authors.lastname: Nurwidya
authors.forename: Suzu
authors.initials: S
authors.lastname: Yae
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Koizumi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Moriyama
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Seyama
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Takahashi
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D016211:Transforming Growth Factor alpha; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D000077156:Gefitinib