研究者詳細 - 諏澤　憲

論文 - 諏澤　憲

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Yesl is the key molecule for the resistance to trastuzumab in breast cancer, and dasatinib overcomes the resistance 査読

Hiromasa Yamamoto, Tatsuaki Takeda, Hirotaka Kanzaki, Ken Suzawa, Kei Namba, Hiroki Sato, Hidejiro Torigoe, Mototsugu Watanabe, Yuho Maki, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi, Yoshihisa Kitamura, Toshiaki Sendo, Shinichi Toyooka

CANCER RESEARCH 76 2016年7月

Establishment and molecular characterization of cell lines from Japanese patients with malignant pleural mesothelioma. 査読国際誌

Ken Suzawa, Hiromasa Yamamoto, Tomoyuki Murakami, Hideki Katayama, Masashi Furukawa, Kazuhiko Shien, Shinsuke Hashida, Kazunori Okabe, Keisuke Aoe, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Yusuke Mimura, Shinichi Toyooka, Shinichiro Miyoshi

Oncology letters 11 ( 1 ) 705 - 712 2016年1月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）

Malignant pleural mesothelioma (MPM) is an aggressive disease that is resistant to conventional therapies. Cell lines are useful models for studying the biological characteristics of tumors; therefore, the establishment of MPM cell lines is valuable for exploring novel therapeutic strategies for MPM. In the present study, 4 MPM cell lines (YUMC8, YUMC44, YUMC63, and YUMC64) were established, which consisted of 2 epithelioid and 2 sarcomatoid mesothelioma histological subtypes, from Japanese patients with MPM. The DNA methylation status, mutations, copy number gains, protein expression of representative genes, and the sensitivity to several drugs were examined in these 4 cell lines. Methylation of P16 was demonstrated in 3/4 cell lines, in which the protein expression of p16 was lost. Methylation of RASSF1A was observed in 3/4 cell lines. Copy number gains of EGFR, HER2 or MET were not detected in the 4 cell lines. Mutations in various genes, including EGFR, KRAS, HER2, BRAF, and PIK3CA, which are frequently detected in non-small cell lung cancer, were not detected in the 4 cell lines. microRNA-34b/c is a direct transcriptional target of p53 and is often silenced in MPM by promoter methylation. In the present study, miR-34b/c was heavily methylated in 2/4 established MPM cell lines. For cell adhesion molecules, E-cadherin expression was detected in the 2 epithelioid MPM cell lines, whereas N-cadherin expression was detected in all 4 established cell lines by western blotting. Vimentin was strongly expressed in the 2 sarcomatoid MPM cell lines. None of the established MPM cell lines demonstrated significant responses to the drugs tested, including NVP-AUY922, 17-DMAG, Trichostatin A, and Vorinostat. Although novel molecular findings were not observed in the current characterization of these MPM cell lines, these lines will be useful for future extensive analyses of the biological behavior of MPM and the development of novel therapeutic strategies.

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Antitumor effect of afatinib, as a human epidermal growth factor receptor 2-targeted therapy, in lung cancers harboring HER2 oncogene alterations. 査読国際誌

Ken Suzawa, Shinichi Toyooka, Masakiyo Sakaguchi, Mizuki Morita, Hiromasa Yamamoto, Shuta Tomida, Tomoaki Ohtsuka, Mototsugu Watanabe, Shinsuke Hashida, Yuho Maki, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi

Cancer science 107 ( 1 ) 45 - 52 2016年1月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）

Human epidermal growth factor receptor 2 (HER2) is a member of the HER family of proteins containing four receptor tyrosine kinases. It plays an important role in the pathogenesis of certain human cancers. In non-small-cell lung cancer (NSCLC), HER2 amplification or mutations have been reported. However, little is known about the benefit of HER2-targeted therapy for NSCLCs harboring HER2 alterations. In this study, we investigated the antitumor effect of afatinib, an irreversible epidermal growth factor receptor (EGFR)-HER2 dual inhibitor, in lung cancers harboring HER2 oncogene alterations, including novel HER2 mutations in the transmembrane domain, which we recently identified. Normal bronchial epithelial cells, BEAS-2B, ectopically overexpressing wild-type HER2 or mutants (A775insYVMA, G776VC, G776LC, P780insGSP, V659E, and G660D) showed constitutive autophosphorylation of HER2 and activation of downstream signaling. They were sensitive to afatinib, but insensitive to gefitinib. Furthermore, we examined the antitumor activity of afatinib and gefitinib in several NSCLC cell lines, and investigated the association between their genetic alterations and sensitivity to afatinib treatment. In HER2-altered NSCLC cells (H2170, Calu-3, and H1781), afatinib downregulated the phosphorylation of HER2 and EGFR as well as their downstream signaling, and induced an antiproliferative effect through G1 arrest and apoptotic cell death. In contrast, HER2- or EGFR-non-dependent NSCLC cells were insensitive to afatinib. In addition, these effects were confirmed in vivo by using a xenograft mouse model of HER2-altered lung cancer cells. Our results suggest that afatinib is a therapeutic option as a HER2-targeted therapy for NSCLC harboring HER2 amplification or mutations.

DOI： 10.1111/cas.12845

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Acquisition of cancer stem cell-like properties in non-small cell lung cancer with acquired resistance to afatinib. 査読国際誌

Shinsuke Hashida, Hiromasa Yamamoto, Kazuhiko Shien, Yuichiro Miyoshi, Tomoaki Ohtsuka, Ken Suzawa, Mototsugu Watanabe, Yuho Maki, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi, Shinichi Toyooka

Cancer science 106 ( 10 ) 1377 - 84 2015年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Afatinib is an irreversible epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that is known to be effective against the EGFR T790M variant, which accounts for half of the mechanisms of acquired resistance to reversible EGFR-TKIs. However, acquired resistance to afatinib was also observed in clinical use. Thus, elucidating and overcoming the mechanisms of resistance are important issues in the treatment of non-small cell lung cancer. In this study, we established various afatinib-resistant cell lines and investigated the resistance mechanisms. EGFR T790M mutations were not detected using direct sequencing in established resistant cells. Several afatinib-resistant cell lines displayed MET amplification, and these cells were sensitive to the combination of afatinib plus crizotinib. As a further investigation, a cell line that acquired resistance to afatinib plus crizotinib, HCC827-ACR, was established from one of the MET amplified-cell lines. Several afatinib-resistant cell lines including HCC827-ACR displayed epithelial-to-mesenchymal transition (EMT) features and epigenetic silencing of miR-200c, which is a suppresser of EMT. In addition, these cell lines also exhibited overexpression of ALDH1A1 and ABCB1, which are putative stem cell markers, and resistance to docetaxel. In conclusion, we established afatinib-resistant cells and found that MET amplification, EMT, and stem cell-like features are observed in cells with acquired resistance to EGFR-TKIs. This finding may provide clues to overcoming resistance to EGFR-TKIs.

DOI： 10.1111/cas.12749

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Distant Bystander Effect of REIC/Dkk-3 Gene Therapy through Immune System Stimulation in a Murine Model of Thoracic Malignancies 査読

Ken Suzawa, Kazuhiko Shien, Peng Huang, Masakiyo Sakaguchi, Masami Watanabe, Shinsuke Hashida, Junichi Soh, Hiromasa Yamamoto, Yuho Maki, Hiroaki Asano, Kazunori Tsukuda, Yasutomo Nasu, Hiromi Kumon, Shinichiro Miyoshi, Shinichi Toyooka

JOURNAL OF THORACIC ONCOLOGY 10 ( 9 ) S599 - S599 2015年9月

Anti-tumor effect of Dasatinib in HER2 positive breast cancer with Trastuzumab resistance 査読

Tatsuaki Takeda, Hirotaka Kanzaki, Shinichi Toyooka, Mototsugu Watanabe, Tomoaki Ohtsuka, Ken Suzawa, Shinsuke Hashida, Yuho Maki, Hiromasa Yamamoto, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi, Yoshihisa Kitamura, Toshiaki Sendo

CANCER RESEARCH 75 2015年8月

Anti-tumor effect of afatinib, an irreversible EGFR/HER2 dual inhibitor, in lung cancers harboring HER2 oncogene 査読

Ken Suzawa, Shinichi Toyooka, Masakiyo Sakaguchi, Tomoaki Ohtsuka, Mototsugu Watanabe, Shinsuke Hashida, Yuho Maki, Hiromasa Yamamoto, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi

CANCER RESEARCH 75 2015年8月

Identification of a novel binding protein playing a critical role in HER2 activation in lung cancer cells 査読

Tomoaki Ohtsuka, Masakiyo Sakaguchi, Katsuyoshi Takata, Shinsuke Hashida, Mototsugu Watanabe, Ken Suzawa, Yuho Maki, Hiromasa Yamamoto, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi, Shinichi Toyooka

CANCER RESEARCH 75 2015年8月

Pneumocephalus and chylothorax complicating vertebrectomy for lung cancer. 査読国際誌

Seiichiro Sugimoto, Masato Tanaka, Ken Suzawa, Hitoshi Nishikawa, Shinichi Toyooka, Takahiro Oto, Toshifumi Ozaki, Shinichiro Miyoshi

The Annals of thoracic surgery 99 ( 4 ) 1425 - 8 2015年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Pneumocephalus is a rare, but potentially fatal complication of thoracic surgery. We describe a case of successful management of pneumocephalus complicated by persistent chylothorax developing after en bloc partial vertebrectomy performed after induction chemoradiotherapy for lung cancer invading the spine. Surgical treatment should be considered for pneumocephalus complicated by any condition requiring persistent chest drainage.

DOI： 10.1016/j.athoracsur.2014.05.098

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Hsp90 inhibitor NVP-AUY922 enhances the radiation sensitivity of lung cancer cell lines with acquired resistance to EGFR-tyrosine kinase inhibitors. 査読国際誌

Shinsuke Hashida, Hiromasa Yamamoto, Kazuhiko Shien, Tomoaki Ohtsuka, Ken Suzawa, Yuho Maki, Masashi Furukawa, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi, Susumu Kanazawa, Shinichi Toyooka

Oncology reports 33 ( 3 ) 1499 - 504 2015年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

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.

DOI： 10.3892/or.2015.3735

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Asymptomatic but functional paraganglioma of the posterior mediastinum. 査読国際誌

Ken Suzawa, Hiromasa Yamamoto, Koichi Ichimura, Shinichi Toyooka, Shinichiro Miyoshi

The Annals of thoracic surgery 97 ( 3 ) 1077 - 80 2014年3月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）

A 72-year-old woman was referred to our hospital because of a posterior mediastinal tumor. On the basis of detailed imaging tests, including (123)I-metaiodobenzylguanidine single photon emission computed tomography-computed tomography, and elevated values of catecholamines in the plasma and urine, the tumor was diagnosed as a functional mediastinal paraganglioma even in the absence of symptoms. After preoperative blood pressure control, surgical resection was performed. During the operation, the systemic blood pressure increased transiently as a result of surgical manipulation of the tumor. Soon after the tumor was removed, the patient conversely experienced hypotension. The postoperative course was uneventful, and pathologic diagnosis revealed a paraganglioma.

DOI： 10.1016/j.athoracsur.2013.06.100

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Thoracoscopic lobectomy as salvage surgery for local recurrence of non-small cell lung cancer after carbon ion radiotherapy in an initially operable patient. 査読

Seiichiro Sugimoto, Shinichi Toyooka, Ken Suzawa, Kouichi Ichimura, Osamu Fujii, Shinichiro Miyoshi

Annals of thoracic and cardiovascular surgery : official journal of the Association of Thoracic and Cardiovascular Surgeons of Asia 20 Suppl 501 - 4 2014年

記述言語：英語掲載種別：研究論文（学術雑誌）

Carbon ion radiotherapy (CIRT) for patients with early-stage non-small cell lung cancer (NSCLC) has recently provided favorable local control with very few toxic reactions. Because CIRT for NSCLC has been mostly performed for elderly or inoperable patients, salvage surgery for NSCLC after CIRT has rarely been reported. We describe a case of complete thoracoscopic right upper lobectomy with mediastinal lymphadenectomy performed as salvage surgery for local recurrence of stage IA NSCLC after CIRT in an initially operable patient who had refused surgery 27 months previously. Pleural adhesions caused by CIRT were localized to the pulmonary apex and the central pulmonary structures were intact at the time of the salvage surgery, which allowed us to successfully perform thoracoscopic lobectomy without any complications. Thus, salvage surgery for NSCLC after CIRT may be feasible in an initially operable patient, as CIRT appears to be unlikely to cause any difficulties in the salvage surgery.

DOI： 10.5761/atcs.cr.13-00223

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