title: Hsp90 inhibitor NVP-AUY922 enhances the radiation sensitivity of lung cancer cell lines with acquired resistance to EGFR-tyrosine kinase inhibitors.
abstract: Acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is a critical issue that needs to be overcome in the treatment of patients with non-small cell lung cancer (NSCLC) harboring EGFR activating mutations. EGFR and AKT are client proteins of the 90-kDa heat shock protein (Hsp90). Therefore, it was hypothesized that the use of Hsp90 inhibitors might allow the resistance to EGFR-TKIs to be overcome. Furthermore, Hsp90 inhibitors are known to function as radiosensitizers in various types of cancer. In the present study, we evaluated the radiosensitizing effect of the novel Hsp90 inhibitor, NVP-AUY922 (AUY), on NSCLC cell lines harboring EGFR activating mutations and showing acquired resistance to EGFR-TKIs via any of several mechanisms. We used HCC827 and PC-9, which are NSCLC cell lines harboring EGFR exon 19 deletions, and gefitinib-resistant sublines derived from the same cell lines with T790M mutation, MET amplification or stem-cell like properties. AUY was more effective against the gefitinib-resistant sublines with T790M mutation and MET amplification than against the parental cell lines, although the subline with stem cell-like properties showed more than a 10-fold higher resistance to AUY than the parental cell line. AUY exerted a significant radiosensitizing effect on the parental cell line and the MET-amplified subline through inducing G2/M arrest and inhibition of non-homologous end joining (NHEJ). In contrast, the radiosensitizing effect of AUY was limited on the subline with stem cell-like properties, in which it did not induce G2/M arrest or inhibition of NHEJ. In conclusion, combined inhibition of Hsp90 plus radiation was effective, and therefore a promising treatment alternative for overcoming major EGFR-TKI resistance, such as that induced by T790M mutation or MET amplification. However, other approaches are required to overcome minor resistance to EGFR-TKIs, such as that observed in cells with stem cell-like properties.
authors.affiliation: Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Hashida
authors.affiliation: Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Shien
authors.affiliation: Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Ohtsuka
authors.affiliation: Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Suzawa
authors.affiliation: Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Yuho
authors.initials: Y
authors.lastname: Maki
authors.affiliation: Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Furukawa
authors.affiliation: Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Soh
authors.affiliation: Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Asano
authors.affiliation: Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Tsukuda
authors.affiliation: Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Miyoshi
authors.affiliation: Department of Radiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Kanazawa
authors.affiliation: Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Toyooka
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D059766:DNA End-Joining Repair / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D000077156:Gefitinib; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000532:radiotherapy*; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D012118:Resorcinols / Q000494:pharmacology*
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; D012118:Resorcinols; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib