title: Prolyl isomerase Pin1 promotes survival in EGFR-mutant lung adenocarcinoma cells with an epithelial-mesenchymal transition phenotype.
abstract: The secondary epidermal growth factor receptor (EGFR) T790M mutation is the most prominent mechanism that confers resistance to first- or second-generation EGFR tyrosine kinase inhibitors (TKIs) in lung cancer treatment. Although third-generation EGFR TKIs can suppress the kinase activity of T790M-positive EGFR, they still cannot eradicate EGFR-mutated cancer cells. We previously reported that a subpopulation of EGFR-mutant lung adenocarcinomas depends on enhanced autophagy, instead of EGFR, for survival, and in this study we explore another mechanism that contributes to TKI resistance. We demonstrate here that an EGFR-mutant lung adenocarcinoma cell line, H1975 (L858R+T790M), has a subset of cells that exhibits an epithelial-mesenchymal transition (EMT) phenotype and can thrive in the presence of third-generation EGFR TKIs. These cells depend on not only autophagy but also on the isomerase Pin1 for survival in vitro, unlike their parental cells. The Pin1 protein was expressed in an EGFR-mutant lung cancer tissue that has undergone partial EMT and acquired resistance to EGFR TKIs, but not its primary tumor. These findings suggest that inhibition of Pin1 activity can be a novel strategy in lung cancer treatment.
authors.affiliation: Department of Molecular Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Sakuma
authors.affiliation: Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Nishikiori
authors.affiliation: Department of Molecular Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Sachie
authors.initials: S
authors.lastname: Hirai
authors.affiliation: Department of Molecular Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Yamaguchi
authors.affiliation: Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Gen
authors.initials: G
authors.lastname: Yamada
authors.affiliation: Department of Thoracic Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Watanabe
authors.affiliation: Department of Surgical Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Hasegawa
authors.affiliation: Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kojima
authors.affiliation: Department of Pathology, Jichi Medical University School of Medicine, Tochigi, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Niki
authors.affiliation: Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Takahashi
mesh_terms: D000178:Acrylamides / Q000494:pharmacology; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000178:Acrylamides; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; C571455:WZ4002; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; D000077156:Gefitinib