AKT apoptosis. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) TNF superfamily. apoptosis TRAIL 2 apoptosis

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2 Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) TNF superfamily apoptosis TRAIL 2 apoptosis TRAIL (epidermal growth factor receptor, EGFR) EGFR EGFR EGFR-TKI) EGFR-TKI EGFR TNFIL-8IL-1IL-1 IFN- PC-9 EGFR-TKI PC-9MET200 PC-9MET1000 EGFR-TKI PC-9/MET EGFR HGF MET EGFR-TKI 1) PC-9/MET TNF-TRAIL 70 TNF-EGFR AKT apoptosis (IAPs) apoptosis EGFR TNF- [Ando K, Ohmori T et al Clin Cancer Res, 2005] TNF-Src EGFR ErbB2 EGFR AKT TRAIL ErbB TRAIL apoptosis MET ErbB TRAIL ErbB TRAIL apoptosis EGFR-TKI TRAIL EGFR active mutationexon 1915 bp del EGFR-TKI PC-9 EGFR-TKI PC-9MET200 PC-9MET1000 HEK293 wild type EGFR active mutation EGFR 293_pEGFR293_p15 MTT assay isobologram EGFR-TKI TRAIL Western blot EGFR homo-, hetero-dimer BS3 dimerization assay

3 ITRAIL EGFR trans-activation PC-9 TRAIL 30 EGFR ErkAkt PC-9MET200 PC-9MET1000 PC-9 EGFR TRAIL PC-9 TRAIL FADD sirna TRAIL EGFR TRAIL EGFR TRAIL FADD trans-activation PC-9 TRAIL DR4 DR5 decoy receptor DcR1 DcR2 TRAIL EGFR homo- hetero-dimer dimerization assay PC-9 TNF TRAIL EGFR dimerization EGFR ligand (anti-egf ab, anti-tgf ab) TRAIL EGFR dimerization TRAIL EGFR ligand EGFR lung cancer? Lung Cancer Feb;71(2): Oki Y, Hirose T, Yamaoka T, Ohmori T, et al Phase II study of S-1, a novel oral fluoropyrimidine, and biweekly administration of docetaxel for previously treated advanced non-small-cell lung cancer. Cancer Chemother Pharmacol. 2011;67(4): Hirose T, Yamaoka T, Ohmori T, et alphase II trial of amrubicin and carboplatin in patients with sensitive or refractory relapsed small-cell lung cancer.lung Cancer. 2011;73(3): Murata Y, Hirose T, Yamaoka T, Ohmori T, et al Phase II trial of the combination of carboplatin and irinotecan in elderly patients with small-cell lung cancer. Eur J Cancer Jun;47(9): Sugiyama T, Hirose T, Yamaoka T, Ohmori T, et alevaluation of the efficacy and safety of the combination of gemcitabine and nedaplatin for elderly patients with advanced non-small-cell lung cancer. Oncology. 2011;81(3-4): Hirose T, Yamaoka T, Ohmori T. et al Relationship of circulating tumor cells to the effectiveness of cytotoxic chemotherapy in patients with metastatic non-small-cell lung cancer. Oncol Res. 2012;20(2-3): Okuda K, Hirose T, Yamaoka T, Ohmori T. et al Evaluation of the safety and efficacy of combination chemotherapy with vinorelbine and Hirose T, Yamaoka T, Ohmori T, et alphase II trial of amrubicin and carboplatin in patients with sensitive or refractory relapsed small-cell lung cancer.lung Cancer Jan 27. [Epub ahead of print] 2. Hirose T, Yamaoka T, Ohmori T, et al Are levels of pro-gastrin-releasing peptide or neuron-specific enolase at relapse prognostic factors after relapse in patients with small-cell platinum agents for patients with non-small cell lung cancer with interstitial lung disease. Anticancer Res (12): Sakai A, Ohmori T, et al Application of a qualitative and quantitative real-time polymerase chain reaction method for detecting genetically modified papaya line 55-1 in papaya products. J Thorac Oncol : Hiroaki Ito, Tohru Ohmori, et al Prognostic impact of the number of viable circulating cells

4 with high telomerase activity in gastric cancer patients: A prospective study. Int J Oncol 45: , ,,,. TNF EGFR. 49 Page159 ( ) 2.,,,,. 49 Page162 ( ) 3.,,,,. 49 Page294 ( ) 4.,,, (SCLC) amrubicincarboplatin II. 49 Page295 ( ) 5. Tsuyoki Kadofuku, Toshimitsu Yamaoka,, Takashi Hirose, Tohru Ohmoriet al: HSP70 specifically binds to 15 bp deletion mutant EGFR and modulates sensitivity to EGFR-TKI. Proceedings of American Association for Cancer Research, Vol , 2011Orland FL, USA 6. : EGFR-TKI ARQ197 Met 15 W Tohru Ohmori, Toshimitsu Yamaoka, Takashi Hirose, et al: HSP70 may cause EGFR-TKIs-resistance due to inhibit drug binding to EGFR in the cell that expressed mutant EGFR 70 (English oral session E-1017), Toshimitsu Yamaoka, Takashi Hirose, Tohru Ohmori, et al: TNF transactivates phospho-tyrosine 1068 of EGFR through TACE/EGFR-ligand dependent mechanism. 70 (P-2051), Ai Irisawa,, Tohru Ohmori, T et al: Expression study of micro RNA in Gefitinib resistant cell lines.70 (P-2095), ,,, IV (CTC) 51 5 Page421( ) 11.,,,, nedaplatin +gemcitabine 51 5 Page486( ) 12.,,,, 51 5 Page495( ) 13.,,,, COPD 51 5 Page516( ) 14.,,,, TACE TNF EGFR. 1 Page323 ( ) 15.,,,, nedaplatin+gemcitabine. 1 Page264( ). 16.,,, vinorelbinecarboplatin II. 1 Page326 ( ) 17.,,,, COPD. 1 Page326

5 ( ). 18.,,,, 1 Page319( ) 19. Tohru Ohmori, Toshimitsu Yamaoka, Takashi Hirose, et al: HSP 70 may cause EGFR-TKIs-resistance due to inhibit drug binding to EGFR in the cells that expressed mutant EGFR. Proceedings of American Association for Cancer Research, #1900, (2012, 04, Chicago) 20. Tohru Ohmori, Toshimitsu Yamaoka, Takashi Hirose, et al. Specific epidermal growth factor receptor autophosphorylation sites promote epithelial cell chemotaxis and restitution. 103rd Annual Meeting of American Association for Cancer Research (2012, 04, Chicago) 21. Tohru Ohmori, Toshimitsu Yamaoka, Takashi Hirose, et al Cancer Vaccination trial with novel multiple peptides in previously treated advanced non-small cell lung cancer. Annual Meeting of American Society of Clinical Oncology (2012, 06, Chicago) 22. Micro RNA 16 S2-4, , Carboplatin+Paclitaxel+Bevacizumab III 52 3 Page ( ) 24., Page2134 ( ) 25., COPD Page775 ( ) 26., Page637 ( ) 27., EGFR Page625 ( ) 28.,. FGFR-TKI Page621( ) 29., Page598 ( ) 30., Page586 ( ) 31. vinorelbinecarboplatin II Page579 ( ) 32. Tohru Ohmori, Toshimitsu Yamaoka, Takashi Hirose, et al: A novel c-met inhibitor, tivantinib, shows an additive growth-inhibitory effect with erlotinib through enhanced degradation of c-met protein via its recycling pathway 19 th International Charles Heidelberger Symposium on Cancer Research P-04, ,, DNA. 113, (375), Toshimitsu Yamaoka, Takashi Hirose, Tohru Ohmori et al The characteristics of an acquired dual resistance to EGFR & MET inhibitors in non-small cell lung cancer, harboring active mutation of EGFR. #5648Annual Meeting 2013, American Association for Cancer Research

6 Washington 35. Masanao Nakashima, Takashi Hirose, Toshimitsu Yamaoka, Tohru Ohmori, et al Clinical benefit of 2nd EGFR-TKI retreatment on overall survival in patients with advanced non-small cell lung cancer 11 P MET EGFR-TKI PC-9 MET The characteristics of dual resistance to EGFR & MET inhibitors in pulmonary adenocarcinoma, PC-9 cells 72 E-2030, SERS Novel methodology of integrated omics analysis by using Surface Enhanced Raman Scattering (SERS): A Preliminary Study Toshihiro Suzuki, Toshimitsu Yamaoka, Tohru Ohmori, et al Contribution of mir-205 in gefitinib-resistant lung cancer cell lines. Annual Meeting 2014, American Association for Cancer Research SanDiego 39. Toshimitsu Yamaoka, Tohru Ohmori, et al TNF transactivation of EGFR protects EGFR-TKI, gefitinib induced pulmonary epithelial cell apoptosis and injury in TNF transgenic mice. #2277 Annual Meeting 2014, American Association for Cancer Research SanDiego 3 1. : (3 ) , EGFR (The mechanisms of resistance to EGFR-TKIs and challenges to overcome resistance in EGFR mutant Non-small cell lung cancer) 39 6 Page (2012.6)