研究者詳細 - 安田　浩之

論文 - 安田　浩之

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Suspected accelerated disease progression after discontinuation of nintedanib in patients with idiopathic pulmonary fibrosis: Two case reports.

Okamori S, Asakura T, Masuzawa K, Yasuda H, Kamata H, Ishii M, Betsuyaku T

Medicine 96 （ 49 ） e9081 2017年12月

査読有り, ISSN 0025-7974

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Characterization of the efficacies of osimertinib and nazartinib against cells expressing clinically relevant epidermal growth factor receptor mutations

Masuzawa, K., Yasuda, H., Hamamoto, J., Nukaga, S., Hirano, T., Kawada, I., Naoki, K., Soejima, K., Betsuyaku, T.

Oncotarget 8 （ 62 ） 105479 - 105491 2017年12月

ISSN 1949-2553

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Suspected accelerated disease progression after discontinuation of nintedanib in patients with idiopathic pulmonary fibrosis: Two case reports

Okamori, S., Asakura, T., Masuzawa, K., Yasuda, H., Kamata, H., Ishii, M., Betsuyaku, T.

Medicine (United States) 96 （ 49 ） e9081 2017年12月

ISSN 1536-5964

RATIONAL: The efficacy of nintedanib, a multitarget receptor tyrosine kinase inhibitor, has been demonstrated in recent randomized controlled trials involving patients with idiopathic pulmonary fibrosis (IPF). However, accelerated disease progression after nintedanib discontinuation has never been reported. PATIENT CONCERNS: We report 2 cases involving patients with a history of IPF who presented with respiratory deterioration at 3 weeks after the discontinuation of nintedanib therapy for IPF. Neither patient fulfilled the definition of "acute exacerbation of IPF" on unilateral computed tomography. DIAGNOSES: Accelerated disease progression after the discontinuation of nintedanib therapy for IPF. INTERVENTIONS: One patient received steroid therapy. The other patient refused to undergo steroid therapy. OUTCOMES: The first patient showed that the affected lobe exhibited volume loss with traction bronchiectasis after receiving steroid therapy, and succumbed to pneumothorax after 3 months. The other patient was transferred to another hospital because of a decline in his general condition. LESSONS: To our knowledge, this report is the first to document accelerated disease progression af

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Non-small cell lung cancer PC-9 cells exhibit increased sensitivity to gemcitabine and vinorelbine upon acquiring resistance to EGFR-tyrosine kinase inhibitors

Hamamoto, J., Yasuda, H., Aizawa, K., Nishino, M., Nukaga, S., Hirano, T., Kawada, I., Naoki, K., Betsuyaku, T. and Soejima, K.

Oncol Lett 14 （ 3 ） 3559 - 3565 2017年09月

ISSN 1792-1074

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (EGFR-TKIs) are widely used for the treatment of non-small cell lung cancers (NSCLCs) harboring EGFR-activating mutations. However, lung cancer cells inevitably acquire resistance to these EGFR-TKIs. The majority of patients whose lung cancer acquires resistance to EGFR-TKIs are subjected to treatment using cytotoxic agents. The present study aimed to determine if lung cancer cells acquiring resistance to EGFR-TKIs also develop altered sensitivity to cytotoxic agents. It was revealed that lung cancer cells that had developed resistance to EGFR-TKIs had increased sensitivity to gemcitabine and vinorelbine compared with EGFR-TKI naive cells. The expression levels of ATP-binding cassette (ABC) transporter genes, including ABCC3, ABCC5 and ABCG2, were observed to be commonly repressed in EGFR-TKI-resistant cells. In addition, two cases were identified in which gemcitabine and vinorelbine exerted marked responses to lung cancers that had acquired resistance to EGFR-TKIs, even with late-line treatment. Therefore, it was proposed that gemcitabine and vinorelbine may be effective agents for patients with lung cancer previously treated with EGFR-TKIs.

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Clinical and pathological characteristics of EGFR mutation in operable early-stage lung adenocarcinoma

Yotsukura, M., Yasuda, H., Shigenobu, T., Kaseda, K., Masai, K., Hayashi, Y., Hishida, T., Ohtsuka, T., Naoki, K., Soejima, K., Betsuyaku, T. and Asamura, H.

Lung Cancer 109 45 - 51 2017年07月

ISSN 1872-8332

OBJECTIVES: Over the past decade, the biological and clinical characteristics of lung cancer with epidermal growth factor receptor (EGFR) mutation have been well studied. However, most studies have focused on advanced inoperable cancer, and not on resected early-stage lung adenocarcinoma. We aimed to elucidate the differences in the clinicopathological characteristics and postoperative prognosis according to the EGFR mutation status in early-stage lung adenocarcinoma. MATERIALS AND METHODS: We retrospectively collected clinical and pathological data from 369 patients with pathological stage I or II lung adenocarcinoma who underwent complete resection. Clinicopathological characteristics and postoperative prognosis were compared depending on the EGFR mutation status, using the Chi-squared test and the log-rank test, respectively. RESULTS AND CONCLUSION: Of the 369 patients, 160 (43.3%) had EGFR mutation, of which 64 (40.0%) were exon 19 deletion (Del-19) and 90 (56.3%) were exon 21 point mutation L858R. Although there was no difference in overall survival (OS) between patients with and without EGFR mutation (p=0.086), tumors with EGFR mutation were associated with a lower consolidation to tumor ratio (CTR) (p <0.001) and a higher incidence of a lepidic growth pattern by pathological evaluation (p <0.001) compared to those without EGFR mutation. Among tumors with EGFR mutation, there was no difference in OS (p=0.140) between Del-19 and L858R. Tumors with L858R were associated with a lower CTR (p=0.046), and tended to have a higher incidence of a lepidic growth pattern by pathological evaluation (p=0.073) compared to those with Del-19. In conclusion, although EGFR mutation status was not a prognostic indicator after surgery in early-stage lung adenocarcinoma, L858R and Del-19 had different radiological and pathological features.

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Effects of the common polymorphism in the human aldehyde dehydrogenase 2 (ALDH2) gene on the lung

Kuroda, A., Hegab, A. E., Jingtao, G., Yamashita, S., Hizawa, N., Sakamoto, T., Yamada, H., Suzuki, S., Ishii, M., Namkoong, H., Asakura, T., Ozaki, M., Yasuda, H., Hamamoto, J., Kagawa, S., Soejima, K. and Betsuyaku, T.

Respir Res 18 （ 1 ） 69 2017年04月

ISSN 1465-993X

BACKGROUND: Aldehyde dehydrogenases (ALDHs) play a major role in detoxification of aldehydes. High expression of ALDHs is a marker for stem cells of many organs including the lungs. A common polymorphism in ALDH2 gene (ALDH2*2) results in inactivation of the enzyme and is associated with alcohol flushing syndrome and increased risk for cardiovascular and Alzheimer's diseases and some cancers. The effect of this ALDH2 polymorphism on the lung and its stem cells has not been thoroughly examined. METHODS: We examined the association between the ALDH2*2 allele and lung function parameters in a population of healthy individuals. We also examined its association with the incidence of asthma and COPD in patient cohorts. We used the in vitro colony forming assay to detect the effect of the polymorphism on lung epithelial stem cells from both primary human surgical samples and Aldh2*2 transgenic (Tg) and Aldh2 -/- mice. Response to acute and chronic lung injuries was compared between wild type (WT), Aldh2*2 Tg and Aldh2 -/- mice. RESULTS: In humans, the ALDH2*2 allele was associated with lower FEV1/FVC in the general population, but not with the development of asthma or COPD. Both the bronchial and lung epithelium carrying the ALDH2*2 allele showed a tendency for lower colony forming efficiency (CFE) compared to ALDH2 allele. In mice, the tracheal epithelial thickness, nuclear density, and number of basal stem cells were significantly lower in Aldh2 -/- and Aldh2*2 Tg adult mice than in WT. Electron microscopy showed significantly increased number of morphologically abnormal mitochondria in the trachea of Aldh2 -/- mice. Aldh2 -/- tracheal and lung cells showed higher ROS levels and fewer functional mitochondria than those from WT mice. No significant differences were detected when tracheal and lung epithelial stem cells were examined for their in vitro CFE. When exposed to chronic cigarette smoke, Aldh2*2 Tg mice were resistant to emphysema development, whereas influenza infection caused more epithelial damage in Aldh2 -/- mice than in WT mice. CONCLUSIONS: ALDH2 polymorphism has several subtle effects on the lungs, some of which are similar to changes observed during normal aging, suggesting a "premature lung aging" effect.

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Amplification of EGFR Wild-Type Alleles in Non-Small Cell Lung Cancer Cells Confers Acquired Resistance to Mutation-Selective EGFR Tyrosine Kinase Inhibitors

Nukaga, S., Yasuda, H., Tsuchihara, K., Hamamoto, J., Masuzawa, K., Kawada, I., Naoki, K., Matsumoto, S., Mimaki, S., Ikemura, S., Goto, K., Betsuyaku, T. and Soejima, K.

Cancer Res 77 （ 8 ） 2078 - 2089 2017年04月

ISSN 1538-7445

EGFR-mutated lung cancers account for a significant subgroup of non-small cell lung cancers overall. Third-generation EGFR tyrosine kinase inhibitors (TKI) are mutation-selective inhibitors with minimal effects on wild-type EGFR. Acquired resistance develops to these agents, however, the mechanisms are as yet uncharacterized. In this study, we report that the Src-AKT pathway contributes to acquired resistance to these TKI. In addition, amplification of EGFR wild-type alleles but not mutant alleles was sufficient to confer acquired resistance. These findings underscore the importance of signals from wild-type EGFR alleles in acquiring resistance to mutant-selective EGFR-TKI. Our data provide evidence of wild-type allele-mediated resistance, a novel concept of acquired resistance in response to mutation-selective inhibitor therapy in cancer treatment. Cancer Res; 77(8); 2078-89. (c)2017 AACR.

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Erlotinib as second- or third-line treatment in elderly patients with advanced non-small cell lung cancer: Keio Lung Oncology Group Study 001 (KLOG001)

Miyawaki, M., Naoki, K., Yoda, S., Nakayama, S., Satomi, R., Sato, T., Ikemura, S., Ohgino, K., Ishioka, K., Arai, D., Namkoong, H., Otsuka, K., Miyazaki, M., Tani, T., Kuroda, A., Nishino, M., Yasuda, H., Kawada, I., Koh, H., Nakamura, M., Terashima, T., Sakamaki, F., Sayama, K., Betsuyaku, T. and Soejima, K.

Mol Clin Oncol 6 （ 3 ） 409 - 414 2017年03月

ISSN 2049-9450

The aim of this study was to assess the efficacy and safety of erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), as second- or third-line treatment for elderly Japanese patients with non-small-cell lung cancer (NSCLC). The patients eligible for this phase II trial were aged >/=70 years, had stage III/IV or recurrent NSCLC, and had previously received 1 or 2 chemotherapy regimens that did not include EGFR-TKIs. The patients received erlotinib at a dose of 150 mg/day. The primary endpoint was overall response rate (ORR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS) and toxicity. A total of 38 patients with a median age of 76 years were enrolled. The majority of the patients were men (66%), had an Eastern Cooperative Oncology Group performance status of 1 (58%), stage IV disease (66%) and adenocarcinoma (74%). Of the 35 patients, 13 (34%) had tumors with EGFR mutations. The ORR was 26.3% (95% confidence interval: 12.1-40.5%) and the disease control rate was 47.4%. The median PFS was 3.7 months and the median OS was 17.3 months. The grade 3 adverse events observed included rash (13%), diarrhea (5%), interstitial pneumonitis (5%), anorexia (3%) and gastrointestinal bleeding (3%). Grade 4 or 5 adverse events were not observed. The median OS did not differ significantly between patients aged <75 years (14.9 months) and those aged >/=75 years (19.0 months; P=0.226). Therefore, erlotinib was found to be effective and well-tolerated in elderly patients with previously treated NSCLC.

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Osimertinib for EGFR T790M mutation-positive non-small cell lung cancer

Soejima, K., Yasuda, H. and Hirano, T.

Expert Rev Clin Pharmacol 10 （ 1 ） 31 - 38 2017年01月

ISSN 1751-2441

INTRODUCTION: Significant advances have been made since the development of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) targeting EGFR mutations in non-small-cell lung cancer (NSCLC), however, lung cancer cells eventually acquire resistance to those agents. Osimertinib (AZD9291) has been developed as 3rd generation EGFR-TKI with activities against sensitizing mutations and T790 M resistance mutation, which account for about 50% of the mechanisms of acquired resistance to 1st or 2nd generation EGFR-TKIs. A recent phase I/II clinical trial with osimertinib for advanced NSCLC patients with known sensitizing EGFR mutations and documented disease progression on prior EGFR-TKIs revealed promising effect with acceptable toxicities. Areas covered: This article summarizes current understanding and available preclinical and clinical data on osimertinib and also discusses future directions. The literature search included PubMed and the latest articles from international conferences. Expert commentary: The development of osimertinib has provided new therapeutic options for NSCLC patients harboring T790 M. Compared with other EGFR-TKIs including rociletinib, osimertinib seems to possess an advantage with respect to the effect and safety profile among existing EGFR-TKIs. However, tumor progression still occurs even when treating with osimertinib. A further understanding of the mechanisms of resistance is eagerly anticipated in order to develop next generation EGFR-TKIs.

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Overcoming EGFR Bypass Signal-Induced Acquired Resistance to ALK Tyrosine Kinase Inhibitors in ALK-Translocated Lung Cancer

Miyawaki, M., Yasuda, H., Tani, T., Hamamoto, J., Arai, D., Ishioka, K., Ohgino, K., Nukaga, S., Hirano, T., Kawada, I., Naoki, K., Hayashi, Y., Betsuyaku, T. and Soejima, K.

Mol Cancer Res 15 （ 1 ） 106 - 114 2017年01月

ISSN 1557-3125

Activation of the EGFR pathway is one of the mechanisms inducing acquired resistance to anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI) such as crizotinib and alectinib. Ceritinib is a highly selective ALK inhibitor and shows promising efficacy in non-small cell lung cancers (NSCLC) harboring the ALK gene rearrangement. However, the precise mechanism underlying acquired resistance to ceritinib is not well-defined. This study set out to clarify the mechanism in ALK-translocated lung cancer and to find the preclinical rationale overcoming EGFR pathway-induced acquired resistance to ALK-TKIs. To this end, ceritinib-resistant cells (H3122-CER) were established from the H3122 NSCLC cell line harboring the ALK gene rearrangement via long-term exposure to ceritinib. H3122-CER cells acquired resistance to ceritinib through EGFR bypass pathway activation. Furthermore, H3122 cells that became resistant to ceritinib or alectinib through EGFR pathway activation showed cross-resistance to other ALK-TKIs. Ceritinib and afatinib combination treatment partially restored the sensitivity to ceritinib. IMPLICATIONS: This study proposes a preclinical rationale to use ALK-TKIs and afatinib combination therapy for ALK-translocated lung cancers that have acquired resistance to ALK-TKIs through EGFR pathway activation. Mol Cancer Res; 15(1); 106-14. (c)2016 AACR.

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Variant CD44 expression is enriching for a cell population with cancer stem cell-like characteristics in human lung adenocarcinoma

Nishino, M., Ozaki, M., Hegab, A. E., Hamamoto, J., Kagawa, S., Arai, D., Yasuda, H., Naoki, K., Soejima, K., Saya, H. and Betsuyaku, T.

J Cancer 8 （ 10 ） 1774 - 1785 2017年

ISSN 1837-9664

Background: Preliminary studies have identified cancer stem cells (CSCs) in various cancers and there are several ongoing clinical studies targeting these cells. CD44 (standard or variant isoforms) and/or aldehyde dehydrogenase (ALDH) expression is the most commonly used markers for the identification of CSCs. The goal of the current study was to examine the ability of CD44v, either alone or in combination with ALDH, to identify CSCs within human lung cancer cells lines. Methods: We examined several lung adenocarcinoma cell lines for the ability of CD44v and/or ALDH expression to enrich for cells with CSC characteristics such as in vitro differential proliferation rate, chemotherapeutic-resistance, tumorsphere formation, and in vivo tumorigenicity. We also compared their in vivo secondary tumor formation, and histological characteristics of their xenograft tumors, and examined their expression of PD-L1, EGFR, xCT, and reactive oxygen species (ROS). Results: Both CD44vhigh/ALDHhigh and CD44vhigh/ALDHlow cells were enriched in cells with CSC characteristics, with the CD44vhigh/ALDHlow cells being more proliferative and more resistant to chemotherapeutics, whereas CD44vhigh/ALDHhigh cells were more efficient in forming tumorspheres in vitro, in making primary xenograft tumors, and in propagating secondary tumors in vivo. Applying stricter sorting gates to select for cells with the highest CD44v/ALDH expression caused the CD44vhigh/ALDHlow cells to lose their high proliferation rates and chemotherapeutic resistance ability, but enriched for the tumorsphere-forming cells among the CD44vhigh/ALDHhigh and CD44vhigh/ALDHlow cells. CD44vhigh expression was associated with PD-L1 and xCT expression in both H1650 and HCC827 cells. This association was not modified by ALDH expression in the H1650 cell line. However, in the HCC827 cell line, ALDH expression was negatively associated with PD-L1 and positively associated with xCT expression. Conclusion: Lung adenocarcinoma cells with high CD44v expression are enriched for CSCs. Addition of ALDH as an enrichment marker bestowed some CSCs characteristics to CD44vhigh/ALDHlow cells and others to CD44vhigh/ALDHhigh cells. We propose that lung adenocarcinoma contains different CSCs, each of them endowed with different CSC characteristics.

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Sternoclavicular joint osteomyelitis extending to lung abscess complicated by Staphylococcal infective endocarditis

Masuzawa, K., Asakura, T., Ishii, M., Yasuda, H., Sugiura, H., Betsuyaku, T.

IDCases 9 36 - 37 2017年

査読有り

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Successful treatment of non-small-cell lung cancer with afatinib and a glucocorticoid following gefitinib- and erlotinib-induced interstitial lung disease: A case report.

Tani T, Naoki K, Asakura T, Hirano T, Suzuki S, Masuzawa K, Hasegawa H, Kuroda A, Yasuda H, Ishii M, Soejima K, Betsuyaku T, Molecular, clinical oncology

Molecular and clinical oncology （Spandidos Publications） 5 （ 4 ） 488 - 490 2016年10月

査読有り, ISSN 2049-9450

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Alectinib as a treatment option following recovery from crizotinib-induced interstitial lung disease in patients with anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer.

Shigenari Nukaga, Katsuhiko Naoki, Tetsuro Kamo, Keita Masuzawa, Hiroyuki Yasuda, Kenzo Soejima, Tomoko Betsuyaku

Molecular and clinical oncology 4 （ 6 ） 1085 - 1087 2016年06月

ISSN 2049-9450

Crizotinib is a tyrosine kinase inhibitor that displays antitumor activity against anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer. However, crizotinib-associated interstitial lung disease (ILD) has been reported as an infrequent, but potentially fatal complication. We herein describe the case of a 63-year-old male patient with ALK-rearranged advanced lung adenocarcinoma. Chest computed tomography (CT) revealed extensive bilateral ground-glass opacity and airspace consolidation with traction bronchiectasis on day 27 of crizotinib therapy. No signs of infection or left heart failure were identified and we considered the lesions to be consistent with crizotinib-induced ILD. Following corticosteroid treatment and discontinuation of crizotinib, CT revealed improvement of ILD, but also showed regrowth of the tumor. Alectinib, a novel alternative ALK inhibitor, was initiated, and has been successfully continued, with neither disease progression nor recurrence of ILD. The present case indicates that alectinib may be considered as an alternative agent in cases of crizotinib-induced ILD, irrespective of the pattern of ILD, i.e., a diffuse alveolar damage (DAD) or non-DAD pattern, with careful observation.

Activation of EGFR Bypass Signaling by TGFalpha Overexpression Induces Acquired Resistance to Alectinib in ALK-Translocated Lung Cancer Cells

Tani, T., Yasuda, H., Hamamoto, J., Kuroda, A., Arai, D., Ishioka, K., Ohgino, K., Miyawaki, M., Kawada, I., Naoki, K., Hayashi, Y., Betsuyaku, T. and Soejima, K.

Mol Cancer Ther 15 （ 1 ） 162 - 71 2016年01月

ISSN 1538-8514

Alectinib is a highly selective ALK inhibitor and shows promising efficacy in non-small cell lung cancers (NSCLC) harboring the EML4-ALK gene rearrangement. The precise mechanism of acquired resistance to alectinib is not well defined. The purpose of this study was to clarify the mechanism of acquired resistance to alectinib in ALK-translocated lung cancer cells. We established alectinib-resistant cells (H3122-AR) from the H3122 NSCLC cell line, harboring the EML4-ALK gene rearrangement, by long-term exposure to alectinib. The mechanism of acquired resistance to alectinib in H3122-AR cells was evaluated by phospho-receptor tyrosine kinase (phospho-RTK) array screening and Western blotting. No mutation of the ALK-TK domain was found. Phospho-RTK array analysis revealed that the phosphorylation level of EGFR was increased in H3122-AR cells compared with H3122. Expression of TGFalpha, one of the EGFR ligands, was significantly increased and knockdown of TGFalpha restored the sensitivity to alectinib in H3122-AR cells. We found combination therapy targeting ALK and EGFR with alectinib and afatinib showed efficacy both in vitro and in a mouse xenograft model. We propose a preclinical rationale to use the combination therapy with alectinib and afatinib in NSCLC that acquired resistance to alectinib by the activation of EGFR bypass signaling.

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A Case of Non-Small Cell Lung Cancer with Possible "Disease Flare" on Nivolumab Treatment.

Shotaro Chubachi, Hiroyuki Yasuda, Hidehiro Irie, Koichi Fukunaga, Katsuhiko Naoki, Kenzo Soejima, Tomoko Betsuyaku

Case reports in oncological medicine 2016 1075641 - 1075641 2016年

Background. Recent clinical trials proven the clinically significant efficacy and tolerability of nivolumab, a programmed death 1 (PD-1) inhibitor, in previously treated patients with non-small cell lung cancer (NSCLC). Case Presentation. Here, we describe the case of a patient who experienced possible "disease flare" immediately after initiation of nivolumab treatment. A 54-year-old man was diagnosed with Stage IIB (T2N1M0) lung adenocarcinoma. After 7 years from recurrence, 10th line chemotherapy, nivolumab, was initiated. Six weeks later, after 3 cycles of nivolumab treatment, rapid lung cancer progression was observed with an increase in the size of the primary lesion, multiple novel nodules on both lungs, and multiple novel brain metastases. Conclusion. We believe that physicians should be made aware that, in a subset of NSCLC patients, disease flare might occur on nivolumab treatment.

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In vitro modeling to determine mutation specificity of EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants in non-small-cell lung cancer

Hirano, T., Yasuda, H., Tani, T., Hamamoto, J., Oashi, A., Ishioka, K., Arai, D., Nukaga, S., Miyawaki, M., Kawada, I., Naoki, K., Costa, D. B., Kobayashi, S. S., Betsuyaku, T. and Soejima, K.

Oncotarget 6 （ 36 ） 38789 - 803 2015年11月

ISSN 1949-2553

EGFR mutated lung cancer accounts for a significant subgroup of non-small-cell lung cancer (NSCLC). Over the last decade, multiple EGFR tyrosine kinase inhibitors (EGFR-TKIs) have been developed to target mutated EGFR. However, there is little information regarding mutation specific potency of EGFR-TKIs against various types of EGFR mutations. The purpose of this study is to establish an in vitro model to determine the "therapeutic window" of EGFR-TKIs against various types of EGFR mutations, including EGFR exon 20 insertion mutations. The potency of 1st (erlotinib), 2nd (afatinib) and 3rd (osimertinib and rociletinib) generation EGFR-TKIs was compared in vitro for human lung cancer cell lines and Ba/F3 cells, which exogenously express mutated or wild type EGFR. An in vitro model of mutation specificity was created by calculating the ratio of IC50 values between mutated and wild type EGFR. The in vitro model identified a wide therapeutic window of afatinib for exon 19 deletions and L858R and of osimertinib and rociletinib for T790M positive mutations. The results obtained with our models matched well with previously reported preclinical and clinical data. Interestingly, for EGFR exon 20 insertion mutations, most of which are known to be resistant to 1st and 2nd generation EGFR-TKIS, osimertinib was potent and presented a wide therapeutic window. To our knowledge, this is the first report that has identified the therapeutic window of osimertinib for EGFR exon 20 insertion mutations. In conclusion, this model will provide a preclinical rationale for proper selection of EGFR-TKIs against clinically-relevant EGFR mutations.

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Prognostic implication of PTPRH hypomethylation in non-small cell lung cancer

安田浩之

ONCOLOGY REPORTS 34 （ 3 ） 1137 - 1145 2015年09月

研究論文（学術雑誌）, ISSN 1021-335X

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Mimicking the niche of lung epithelial stem cells and characterization of several effectors of their in vitro behavior

Hegab, A. E., Arai, D., Gao, J., Kuroda, A., Yasuda, H., Ishii, M., Naoki, K., Soejima, K. and Betsuyaku, T.

Stem Cell Res 15 （ 1 ） 109 - 21 2015年07月

ISSN 1876-7753

The niche surrounding stem cells regulate their fate during homeostasis and after injury or infection. The 3D organoid assay has been widely used to study stem cells behavior based on its capacity to evaluate self-renewal, differentiation and the effect of various medium supplements, drugs and co-culture with supportive cells. We established an assay to study both lung and trachea stem cells in vitro. We characterized their proliferation and differentiation spectrum at baseline then evaluated the effect of co-culturing with fibroblasts and endothelial cells and/or treating with several biologically relevant substances as possible contributors to their niche. We found that lung epithelial (but not tracheal basal) stem cells require co-culture with stromal cells to undergo clonal proliferation and differentiation. Fibroblasts were more efficient than endothelial cells in offering this support and the pattern of support varied based on the tissue origin of the stromal cells. Treating distal lung epithelial or basal stem cells with FGF2, FGF9, FGF10, LIF as well as ALK5 and ROCK inhibitors increased their colony formation efficiency and resulted in variable effects on colonies number, size and differentiation spectrum. This model and findings pave the way for better understanding of lung stem cell niche components and factors that can manipulate lung stem cell behavior.

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Mimicking the niche of lung epithelial stem cells and characterization of several effectors of their in vitro behavior

安田浩之

STEM CELL RESEARCH 15 （ 1 ） 109 - 121 2015年07月

研究論文（学術雑誌）, ISSN 1873-5061

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