Effects of molecular-targeted drugs on nonsmoking-related lung cancer models2012.042015.03A basic studyon malignant mesothelioma pathogenesis by internal radiation exposure of radium contained in the iron-containing protein2011.042013.03EGFR,SP-C,ZD6474,gefitinib,vandetaniv,chemoprevention, Lung cancer, VEGFR,transgenic miceTwenty-five percent of all lung cancer cases are not attributable to smoking. Epidermal growth factor receptor (EGFR) mutations, which are involved in approximately 50% of nonsmoker lung cancer, are positively correlated with responsiveness to gefitinib, and inversely correlated with smoking history. Activating EGFR mutations play a critical role in the carcinogenesis of nonsmoking-related lung cancer. To investigate the chemopreventive effects of gefitinib on nonsmoking-related lung cancer, we generated transgenic mice expressing EGFR L858R in type II pneumocytes constitutively using the surfactant protein-C promoter. The transgenic mice invariably developed atypical adenomatous hyperplasia at age 4 weeks and multifocal adenocarcinoma of varying sizes at age 7 weeks. Notably, the expression levels of phosphorylated and total ErbB2, ErbB3, and thyroid transcription factor-1 were elevated in the transgenic mice compared with wild-type controls at age 3 weeks. Administration of gefitinib to 3-week-old transgenic mice for 1 week before carcinogenesis reduced the amount of phosphorylated EGFR in the lungs of the mice to the baseline level. Gefitinib (5 mg/kg/d; n = 5, 5, and 15) or vehicle (n = 5, 5, and 15) was administered to transgenic mice from age 3 to 8, 13, and 18 weeks, respectively. The numbers of lung tumors in the control and gefitinib-treated groups were 1.75, 5.8, 10.2, and 0 (P < 0.05), respectively. No fatal toxic events occurred in either group, and gefitinib inhibited tumorigenesis completely in this mouse model. These results suggest the utility of molecular targeted chemoprevention against nonsmoking-related lung cancer. REFERENCE To investigate the role of an activating epidermal growth factor receptor (EGFR) mutation in lung cancer, we generated transgenic mice expressing the delE748-A752 mutant version of mouse EGFR driven by the SP-C promoter, which is equivalent to the delE746-A750 mutation found in lung cancer patients. Strikingly, the mice invariably developed multifocal lung adenocarcinomas of varying sizes at between 5 and 6 weeks of age, and they died from tumor progression approximately 2 months later if left untreated. Daily oral administration of the EGFR tyrosine kinase inhibitor (TKI) gefitinib (5 mg/kg/day) reduced the total and phosphorylation levels of EGFR to those in wild-type mouse lung tissue; in addition, it abrogated tumor growth within 1 week and prolonged survival to >30 weeks. Interestingly, phosphorylated ErbB2, ErbB3, and thyroid transcriptional factor-1 increased in the transgenic mice compared with those in wild-type mice. They might play some roles in tumors progression in the transgenic mice. This model will be useful for studying the mechanisms of carcinogenesis, chemoprevention, and acquired resistance to EGFR TKIs in lung cancer patients carrying activating EGFR mutations.1: Ohashi K, Takigawa N, Osawa M, Ichihara E, Takeda H, Kubo T, Hirano S, Yoshino T, Takata M, Tanimoto M, Kiura K. Chemopreventive effects of gefitinib on nonsmoking-related lung tumorigenesis in activating epidermal growth factor receptor transgenic mice. Cancer Res. 2009 Sep 1;69(17):7088-95. 2: Ohashi K, Rai K, Fujiwara Y, Osawa M, Hirano S, Takata K, Kondo E, Yoshino T, Takata M, Tanimoto M, Kiura K. Induction of lung adenocarcinoma in transgenic mice expressing activated EGFR driven by the SP-C promoter. Cancer Sci. 2008 Sep;99(9):1747-53. Chemoprevention of Lung Cancer using Epidermal Growth Factor Receptor Transgenic Mice2007.042009.03AKT A/J mouse MAPK NNK cisplatin lung cancer ras second malignancy 

Photograph

Name

KIURA Katsuyuki

Affiliation

University Hospital of Medicine and Dentistry

Title

Professor

Sex

male

Laboratory address

2-5-1 Shikatacho, Kitaku, Okayama 7008558

Laboratory telephone number

+81-86-235-7230

Laboratory FAX number

+81862328226

E-mail address

E-mail address

Research areas, keyword

Internal Medicine Respiratory System

Research Subject 【 display / non-display

  • Subject:Effects of molecular-targeted drugs on nonsmoking-related lung cancer models

    Object:

  • Subject:A basic studyon malignant mesothelioma pathogenesis by internal radiation exposure of radium contained in the iron-containing protein

  • Subject:Chemoprevention of Lung Cancer using Epidermal Growth Factor Receptor Transgenic Mice

 
 

Research Achievement (Published Thesis) 【 display / non-display

  • Subject:Lung transplant candidates with idiopathic pulmonary fibrosis and long-term pirfenidone therapy: Treatment feasibility influences waitlist survival.

    Language:English

    Kind of Publishing:

    Journal name:Respir Investig. , vol.57 (2) (p.165 - 171)

    Publish date:2018.12

    Author:Tanaka S, Miyoshi K , Higo H, Kurosaki T, Otani S, Sugimoto S, Yamane M , Kiura K, Toyooka S, Oto T .

    Co-writerThe multiple authorship

  • Subject:Rapid and Long-term Response of Pulmonary Pleomorphic Carcinoma to Nivolumab: A Case Report.

    Language:English

    Kind of Publishing:

    Journal name:Intern Med. , vol.58 (7) (p.985 - 989)

    Publish date:2018.12

    Author:Senoo S, Ninomiya T, Makimoto G, Nishii K, Kano H, Watanabe H, Hata Y, Kubo T, Tanaka T , Hotta K, Maeda Y, Kiura K.

    Co-writerThe multiple authorship

  • Subject:A phase II trial of EGFR-TKI readministration with afatinib in advanced non-small-cell lung cancer harboring a sensitive non-T790M EGFR mutation: Okayama Lung Cancer Study Group trial 1403.

    Language:English

    Kind of Publishing:

    Journal name:Cancer Chemother Pharmacol. , vol.82 (6) (p.1031 - 1038)

    Publish date:2018.12

    Author:Oda N, Hotta K, Ninomiya K, Minami D, Ichihara E, Murakami T, Yokoyama T , Ichikawa H, Chikamori K, Takigawa N, Ochi N, Harita S, Maeda Y, Kiura K.

    Co-writerThe multiple authorship

  • Subject:Phase 2 Study of Afatinib Alone or Combined With Bevacizumab in Chemonaive Patients With Advanced Non-Small-Cell Lung Cancer Harboring EGFR Mutations: AfaBev-CS Study Protocol.

    Language:English

    Kind of Publishing:

    Journal name:Clin Lung Cancer. , vol.20 (2) (p.134 - 138)

    Publish date:2018.11

    Author:Ninomiya T, Ishikawa N , Inoue K, Kubo T, Yasugi M, Shibayama T, Maeda T, Fujitaka K, Kodani M, Yokoyama T , Kuyama S, Ochi N, Ueda Y, Miyoshi S , Kozuki T, Amano Y, Kubota T , Sugimoto K, Bessho A, Ishii T , Watanabe K, Oze I, Hotta K, Kiura K.

    Co-writerThe multiple authorship

  • Subject:Study Protocol: Phase-Ib Trial of Nivolumab Combined With Metformin for Refractory/Recurrent Solid Tumors.

    Language:English

    Kind of Publishing:

    Journal name:Clin Lung Cancer. , vol.19 (6) (p.e861 - e864)

    Publish date:2018.11

    Author:Kubo T, Ninomiya T, Hotta K, Kozuki T, Toyooka S, Okada H, Fujiwara T, Udono H , Kiura K.

    Co-writerThe multiple authorship

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