title: The anti-proliferative effect of heat shock protein 90 inhibitor, 17-DMAG, on non-small-cell lung cancers being resistant to EGFR tyrosine kinase inhibitor.
abstract: Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, is frequently observed after initiation of TKIs therapy. Non-small-cell lung cancers (NSCLC) with activating EGFR mutations were reported to be sensitive to heat shock protein 90 (Hsp90) inhibitors regardless of the secondary TKI-resistant T790M mutation. We established EGFR-TKI resistant clones for PC-9 cell lines, harboring EGFR exon 19 deletions, with or without the secondary T790M mutation. We examined the anti-proliferative effect of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), an orally active Hsp90 inhibitor, on the growth of NSCLC cell lines in vitro and in vivo. In MTS assay, the IC(50) values of 17-DMAG for 13 EGFR-mutant cell lines including eight EGFR-TKI resistant cell lines ranged from 0.04 to 0.16 μM while those for seven EGFR-wild type cell lines ranged from 1.6 to 27.4 μM. Western blot analysis revealed that phospho-EGFR, phospho-Akt, phospho-MAPK, cdk4, and cyclin D1 were more readily depleted by 17-DMAG treatment in EGFR-mutant cell lines than in EGFR-wild type cell lines. Cleaved PARP expression confirmed apoptosis in response to 17-DMAG treatment in EGFR-mutant cell lines but not in EGFR-wild type cell lines. In mice xenograft models, 17-DMAG significantly reduced the growth of EGFR-mutant lines irrespective of T790M mutation. These results suggested that 17-DMAG is a potential novel therapeutic agent for NSCLC patients with EGFR mutations with or without EGFR-TKI resistance.
authors.affiliation: Department of Cancer and Thoracic Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho Okayama, Okayama 700-8558, Japan.
authors.forename: Naruyuki
authors.initials: N
authors.lastname: Kobayashi
authors.forename: Shinichi
authors.initials: S
authors.lastname: Toyooka
authors.forename: Junichi
authors.initials: J
authors.lastname: Soh
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Hideaki
authors.initials: H
authors.lastname: Dote
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kawasaki
authors.forename: Hiroki
authors.initials: H
authors.lastname: Otani
authors.forename: Takafumi
authors.initials: T
authors.lastname: Kubo
authors.forename: Masaru
authors.initials: M
authors.lastname: Jida
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Ueno
authors.forename: Midori
authors.initials: M
authors.lastname: Ando
authors.forename: Atsuko
authors.initials: A
authors.lastname: Ogino
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Kiura
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Miyoshi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D009154:Mutation; D011799:Quinazolines / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011799:Quinazolines; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000077156:Gefitinib