研究者詳細 - 諏澤　憲

論文 - 諏澤　憲

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大谷真二, 石原恵, 石上恵美, 松原慧, 清水大, 富岡泰章, 山本治慎, 塩谷俊雄, 諏澤憲, 三好健太郎, 山本寛斉, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

移植 56 ( 1 ) 76 - 76 2021年7月

当院における小児肺移植の成績

大谷真二, 富岡泰章, 松原慧, 清水大, 山本治慎, 塩谷俊雄, 諏澤憲, 三好健太郎, 山本寛斉, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

日本外科学会定期学術集会抄録集 121回 PS - 8 2021年4月

Successful Bronchoscopic Treatment for Postoperative Bronchopleural Fistula Using N-butyl-2-cyanoacrylate (NBCA): Report of a Post-completion Pneumonectomy Case with a History of Induction Chemoradiotherapy Followed by Bilobectomy for Advanced Lung Cancer. 査読

Toshio Shiotani, Hiromasa Yamamoto, Riko Katsube, Yasuaki Tomioka, Ken Suzawa, Kentaroh Miyoshi, Shinji Otani, Mikio Okazaki, Seiichiro Sugimoto, Junichi Soh, Masaomi Yamane, Shinichi Toyooka

Acta medica Okayama 75 ( 1 ) 91 - 94 2021年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Bronchopleural fistula (BPF) is a severe complication following lung resection. We present the case of a patient with a history of advanced lung cancer, who had undergone induction chemoradiotherapy followed by right middle and lower lobectomy, and who developed BPF after completion right pneumonectomy. Although we had covered the bronchial stump with an omental pedicled flap, BPF was found on postoperative day 19. We covered the fistula with n-butyl-2-cyanoacrylate (NBCA) using bronchoscopy. Although we had to repeat the NBCA treatment, we ultimately cured the patient's BPF and no recurrence was observed up to 15.2 months after surgery.

DOI： 10.18926/AMO/61440

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The neutrophil-to-lymphocyte ratio as a novel independent prognostic factor for multiple metastatic lung tumors from various sarcomas. 査読

Hiromasa Yamamoto, Kei Namba, Haruchika Yamamoto, Tomohiro Toji, Junichi Soh, Kazuhiko Shien, Ken Suzawa, Takeshi Kurosaki, Shinji Otani, Mikio Okazaki, Seiichiro Sugimoto, Masaomi Yamane, Katsuhito Takahashi, Toshiyuki Kunisada, Takahiro Oto, Shinichi Toyooka

Surgery today 51 ( 1 ) 127 - 135 2021年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: Sarcomas are among the most refractory malignant tumors and often recur as pulmonary metastasis. Although the presence of a high neutrophil-to-lymphocyte ratio (NLR) has been associated with the prognosis of several malignancies, the relationship between the NLR and sarcoma with pulmonary metastasis is unclear. We investigated the impact of the NLR in patients who underwent surgical resection for metastatic lung tumors from various sarcomas. METHODS: The subjects of this retrospective study were 158 patients with metastatic lung tumors from various sarcomas, who underwent initial pulmonary metastasectomy between 2006 and 2015. We examined the clinicopathological variables, including the NLR and the characteristics of surgical procedures. Survival was estimated by the Kaplan-Meier method and prognostic factors were evaluated by multivariate analysis. RESULTS: Multivariate analysis revealed significantly better survival of the group with an NLR < 2.26 immediately before the most recent pulmonary metastasectomy, in addition to such factors as the largest resected lesion being < 22 mm, a disease-free interval of > 2 years, and 3 or more pulmonary metastasectomies. CONCLUSION: The NLR immediately before the most recent pulmonary metastasectomy is a novel independent prognostic factor, which may be helpful when considering repeated pulmonary metastasectomy.

DOI： 10.1007/s00595-020-02093-5

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The heterodimer S100A8/A9 is a potent therapeutic target for idiopathic pulmonary fibrosis. 査読国際誌

Kota Araki, Rie Kinoshita, Nahoko Tomonobu, Yuma Gohara, Shuta Tomida, Yuta Takahashi, Satoru Senoo, Akihiko Taniguchi, Junko Itano, Ken-Ichi Yamamoto, Hitoshi Murata, Ken Suzawa, Kazuhiko Shien, Hiromasa Yamamoto, Mikio Okazaki, Seiichiro Sugimoto, Kouichi Ichimura, Masahiro Nishibori, Nobuaki Miyahara, Shinichi Toyooka, Masakiyo Sakaguchi

Journal of molecular medicine (Berlin, Germany) 99 ( 1 ) 131 - 145 2021年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

In patients with interstitial pneumonia, pulmonary fibrosis is an irreversible condition that can cause respiratory failure. Novel treatments for pulmonary fibrosis are necessary. Inflammation is thought to activate lung fibroblasts, resulting in pulmonary fibrosis. Of the known inflammatory molecules, we have focused on S100A8/A9 from the onset of inflammation to the subsequent progression of inflammation. Our findings confirmed the high expression of S100A8/A9 in specimens from patients with pulmonary fibrosis. An active role of S100A8/A9 was demonstrated not only in the proliferation of fibroblasts but also in the fibroblasts' differentiation to myofibroblasts (the active form of fibroblasts). S100A8/A9 also forced fibroblasts to upregulate the production of collagen. These effects were induced via the receptor of S100A8/A9, i.e., the receptor for advanced glycation end products (RAGE), on fibroblasts. The anti-S100A8/A9 neutralizing antibody inhibited the effects of S100A8/A9 on fibroblasts and suppressed the progression of fibrosis in bleomycin (BLM)-induced pulmonary fibrosis mouse model. Our findings strongly suggest a crucial role of S100A8/A9 in pulmonary fibrosis and the usefulness of S100A8/A9-targeting therapy for fibrosis interstitial pneumonia. HIGHLIGHTS: S100A8/A9 level is highly upregulated in the IPF patients' lungs as well as the blood. S100A8/A9 promotes not only the growth of fibroblasts but also differentiation to myofibroblasts. The cell surface RAGE acts as a crucial receptor to the extracellular S100A8/A9 in fibroblasts. The anti-S100A8/A9 antibody effectively suppresses the progression of IPF in a mouse model. In idiopathic pulmonary fibrosis (IPF), S100A8/A9, a heterodimer composed of S100A8 and S100A9 proteins, plays a crucial role in the onset of inflammation and the subsequent formation of a feed-forward inflammatory loop that promotes fibrosis. (1) The local, pronounced increase in S100A8/A9 in the injured inflammatory lung region-which is provided mainly by the activated neutrophils and macrophages-exerts strong inflammatory signals accompanied by dozens of inflammatory soluble factors including cytokines, chemokines, and growth factors that further act to produce and secrete S100A8/A9, eventually making a sustainable inflammatory circuit that supplies an indefinite presence of S100A8/A9 in the extracellular space with a mal-increased level. (2) The elevated S100A8/A9 compels fibroblasts to activate through receptor for advanced glycation end products (RAGE), one of the major S100A8/A9 receptors, resulting in the activation of NFκB, leading to fibroblast mal-events (e.g., elevated cell proliferation and transdifferentiation to myofibroblasts) that actively produce not only inflammatory cytokines but also collagen matrices. (3) Finally, the S100A8/A9-derived activation of lung fibroblasts under a chronic inflammation state leads to fibrosis events and constantly worsens fibrosis in the lung. Taken together, these findings suggest that the extracellular S100A8/A9 heterodimer protein is a novel mainstay soluble factor for IPF that exerts many functions as described above (1-3). Against this background, we herein applied the developed S100A8/A9 neutralizing antibody to prevent IPF. The IPF imitating lung fibrosis in an IPF mouse model was effectively blocked by treatment with the antibody, leading to enhanced survival. The developed S100A8/A9 antibody, as an innovative novel biologic, may help shed light on the difficulties encountered with IPF therapy in clinical settings.

DOI： 10.1007/s00109-020-02001-x

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Effect of isoflavones on breast cancer cell development and their impact on breast cancer treatments. 査読国際誌

Minami Hatono, Hirokuni Ikeda, Yoko Suzuki, Yukiko Kajiwara, Kengo Kawada, Takahiro Tsukioki, Mariko Kochi, Ken Suzawa, Takayuki Iwamoto, Hiromasa Yamamoto, Tadahiko Shien, Masaomi Yamane, Naruto Taira, Hiroyoshi Doihara, Shinichi Toyooka

Breast cancer research and treatment 185 ( 2 ) 307 - 316 2021年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: Epidemiological studies have suggested that intake of soy isoflavones is associated with a reduced risk of development of breast cancer and an improved prognosis in patients with breast cancer. In addition, basic research has demonstrated the antitumor effects of these compounds on breast cancer cell lines. However, the detailed effects of the intake of equol, which is one of the metabolites of the soy isoflavones, are yet to be clarified on the risk of development and recurrence of breast cancer and its interactions with drugs used for treating breast cancer. This study aimed to determine the antitumor effects of equol and investigate the impact of adding equol to therapeutic agents for breast cancer using breast cancer cell lines. METHODS: We examined the antitumor effect of equol on breast cancer cell lines using MTS assay. We also studied the combined effect of equol and the existing hormonal or chemotherapeutic agents using combination index. We evaluated the expressions of the related proteins by Western blot analysis and correlated the findings with the antitumor effect. RESULTS: Equol showed bi-phasic protumor and antitumor effects; at a low concentration, it promoted the tumor growth in hormone receptor-positive cell lines, whereas antitumor effects were generally observed when an excessive amount of dose unexpected in the blood and the tissue was administered. When used with tamoxifen, equol might have some antagonistic effect, although it depends on equol concentration and the type of cancer cells. CONCLUSIONS: We confirmed that equol has dual action, specifically a tumor growth-promoting effect and an antitumor effect. Although the results suggested that equol might exert an antagonistic effect against tamoxifen depending on the concentration, equol did not exert an antagonistic effect on other therapeutic agents.

DOI： 10.1007/s10549-020-05957-z

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RET inhibition in novel patient-derived models of RET-fusion positive lung adenocarcinoma reveals a role for MYC upregulation. 査読国際誌

Takuo Hayashi, Igor Odintsov, Roger S Smith, Kota Ishizawa, Allan J W Liu, Lukas Delasos, Christopher Kurzatkowski, Huichun Tai, Eric Gladstone, Morana Vojnic, Shinji Kohsaka, Ken Suzawa, Zebing Liu, Siddharth Kunte, Marissa S Mattar, Inna Khodos, Monika A Davare, Alexander Drilon, Emily Cheng, Elisa de Stanchina, Marc Ladanyi, Romel Somwar

Disease models & mechanisms 2020年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Multi-kinase RET inhibitors, such as cabozantinib and RXDX-105, are active in lung cancer patients with RET fusions; however, the overall response rates to these two drugs are unsatisfactory compared to other targeted therapy paradigms. Moreover, these inhibitors may have different efficacies against RET rearrangements depending on the upstream fusion partner. A comprehensive preclinical analysis of the efficacy of RET inhibitors is lacking due to a paucity of disease models harboring RET rearrangements. Here we generated two new patient-derived xenograft (PDX) models, one new patient-derived cell line, one PDX-derived cell line, and several isogenic cell lines with RET fusions. Using these models, we re-examined the efficacy and mechanism of action of cabozantinib and found that this RET inhibitor was effective at blocking growth of cell lines, activating caspase 3/7 and inhibiting activation of ERK and AKT. Cabozantinib treatment of mice bearing RET-fusion-positive cell line xenografts and two PDXs significantly reduced tumor proliferation without adverse toxicity. Moreover, cabozantinib was effective at reducing growth of a lung cancer PDX that was not responsive to RXDX-105. Transcriptomic analysis of lung tumors and cell lines with RET alterations showed activation of a MYC signature and this was suppressed by treatment of cell lines with cabozantinib. MYC protein levels were rapidly depleted following cabozantinib treatment. Taken together, our results demonstrate that cabozantinib is an effective agent in preclinical models harboring RET rearrangements with three different 5' fusion partners (CCDC6, KIF5B and TRIM33). Notably, we identify MYC as a protein that is upregulated by RET expression and down-regulated by cabozantinib treatment, opening up potentially new therapeutic avenues for combinatorial targeting RET-fusion driven lung cancers. The novel RET fusion-dependent preclinical models described herein represent valuable tools for further refinement of current therapies and the evaluation of novel therapeutic strategies.

DOI： 10.1242/dmm.047779

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Prognostic nutrition index affects the prognosis of patients undergoing trimodality therapy for locally advanced non-small cell lung cancer. 査読

Junichi Soh, Ken Suzawa, Kazuhiko Shien, Shinji Otani, Hiromasa Yamamoto, Mikio Okazaki, Seiichiro Sugimoto, Kuniaki Katsui, Masaomi Yamane, Katsuyuki Kiura, Susumu Kanazawa, Shinichi Toyooka

Surgery today 50 ( 12 ) 1610 - 1618 2020年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: Trimodality therapy, comprised of induction chemoradiotherapy (iCRT) followed by surgery, is a highly invasive treatment option for locally advanced non-small cell lung cancers (LA-NSCLCs; defined as a heterogenous disease). We conducted this study to investigate the prognostic nutritional index (PNI) of LA-NSCLC patients undergoing trimodality therapy, which has not been studied in detail before. METHODS: The subjects of this retrospective study were 127 patients who underwent trimodality therapy between 1999 and 2016. We measured the PNI at three points: before iCRT (pre-iCRT), before the operation, and after the operation. RESULTS: PNIs decreased significantly as treatment progressed. Patients with clinical T3/4 (cT3/4) disease had a significantly lower PNI than those with cT1/2 disease, but the extent of lymph-node metastasis did not affect the PNI at any point. Using the cut-off values of receiver-operating curve analyses, multivariable analyses revealed that a high PNI pre-iCRT correlated significantly with a better survival of LA-NSCLC patients, especially those with cT3/4 disease (hazard ratio 3.84; 95% confidential interval 1.34-12.5, P = 0.012). CONCLUSIONS: Measuring the PNI before trimodality therapy is important for predicting the clinical outcome of patients with LA-NSCLC, with differing predictive ability according to the disease extent. Perioperative intensive nutritional intervention must be considered for patients who undergo trimodality therapy for LA-NSCLC.

DOI： 10.1007/s00595-020-02067-7

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岡崎幹生, 諏澤憲, 三好健太郎, 大谷真二, 山本寛斉, 杉本誠一郎, 山根正修, 豊岡伸一

肺癌 60 ( 6 ) 464 - 464 2020年10月

集学的治療が行われた局所進行肺癌患者における末梢血好中球/リンパ球比(NLR)の予後的意義について

津高慎平, 山本寛斉, 諏澤憲, 三好健太郎, 大谷真二, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

肺癌 60 ( 6 ) 658 - 658 2020年10月

ハイリスク症例をいかに手術に繋げるか? 導入放射線化学療法後の局所進行非小細胞肺癌に対する手術後に反回神経麻痺を発症した症例の検討

杉本誠一郎, 諏澤憲, 富岡泰章, 塩谷俊雄, 三好健太郎, 大谷真二, 山本寛斉, 岡崎幹生, 山根正修, 豊岡伸一

肺癌 60 ( 6 ) 492 - 492 2020年10月

高分化腺癌-いつ切るの? すりガラス成分を有する小型肺癌に対する治療の至適介入時期

諏澤憲, 三好健太郎, 大谷真二, 山本寛斉, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

肺癌 60 ( 6 ) 484 - 484 2020年10月

非小細胞肺癌手術症例と末梢血リンパ球/単球比とその継時的変化の関連の検討

富岡泰章, 山本寛斉, 塩谷俊雄, 諏澤憲, 三好健太郎, 大谷真二, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

肺癌 60 ( 6 ) 587 - 587 2020年10月

85歳以上高齢者肺癌手術の問題と課題について多施設共同研究の結果から

葉山牧夫, 藤原俊哉, 平見有二, 渡邉元嗣, 片岡正文, 西川仁士, 諏澤憲, 山本寛斉, 岡崎幹生, 豊岡伸一

肺癌 60 ( 6 ) 547 - 547 2020年10月

間質性肺炎合併肺癌:To treat, or not to treat? 間質性肺炎合併肺癌に対する外科的治療

山本寛斉, 松原慧, 富岡泰章, 塩谷俊雄, 諏澤憲, 三好健太郎, 大谷真二, 岡崎幹生, 杉本誠一郎, 山根正修, 豊岡伸一

肺癌 60 ( 6 ) 481 - 481 2020年10月

Overcoming epithelial-mesenchymal transition-mediated drug resistance with monensin-based combined therapy in non-small cell lung cancer. 査読国際誌

Kosuke Ochi, Ken Suzawa, Shuta Tomida, Kazuhiko Shien, Jui Takano, Shunsaku Miyauchi, Tatsuaki Takeda, Akihiro Miura, Kota Araki, Kentaro Nakata, Hiromasa Yamamoto, Mikio Okazaki, Seiichiro Sugimoto, Tadahiko Shien, Masaomi Yamane, Kazuo Azuma, Yoshiharu Okamoto, Shinichi Toyooka

Biochemical and biophysical research communications 529 ( 3 ) 760 - 765 2020年8月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: The epithelial-mesenchymal transition (EMT) is a key process in tumor progression and metastasis and is also associated with drug resistance. Thus, controlling EMT status is a research of interest to conquer the malignant tumors. MATERIALS AND METHODS: A drug repositioning analysis of transcriptomic data from a public cell line database identified monensin, a widely used in veterinary medicine, as a candidate EMT inhibitor that suppresses the conversion of the EMT phenotype. Using TGF-β-induced EMT cell line models, the effects of monensin on the EMT status and EMT-mediated drug resistance were assessed. RESULTS: TGF-β treatment induced EMT in non-small cell lung cancer (NSCLC) cell lines and the EGFR-mutant NSCLC cell lines with TGF-β-induced EMT acquired resistance to EGFR-tyrosine kinase inhibitor. The addition of monensin effectively suppressed the TGF-β-induced-EMT conversion, and restored the growth inhibition and the induction of apoptosis by the EGFR-tyrosine kinase inhibitor. CONCLUSION: Our data suggested that combined therapy with monensin might be a useful strategy for preventing EMT-mediated acquired drug resistance.

DOI： 10.1016/j.bbrc.2020.06.077

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Pulmonary aspergillosis as a late complication after surgery for locally advanced non-small cell lung cancer treated with induction chemoradiotherapy. 査読

Seiichiro Sugimoto, Junichi Soh, Ken Suzawa, Kentaroh Miyoshi, Shinji Otani, Hiromasa Yamamoto, Mikio Okazaki, Masaomi Yamane, Takahiro Oto, Susumu Kanazawa, Katsuyuki Kiura, Shinichi Toyooka

Surgery today 50 ( 8 ) 863 - 871 2020年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: Some long-term survivors after surgery for locally advanced non-small cell lung cancer (NSCLC) treated with induction chemoradiotherapy (trimodality treatment) develop chronic pulmonary aspergillosis (CPA). The aim of our study was to assess the characteristics and outcomes of CPA that develops after trimodality treatment. METHODS: We retrospectively reviewed the data of 187 NSCLC patients who underwent trimodality treatment between 1999 and 2018. RESULTS: Six male ever-smoker patients developed CPA. All 6 patients had undergone extended resection for NSCLC and had a history of either adjuvant chemotherapy (n = 3) or radiation pneumonitis (n = 4). Among the 4 patients with CPA localized in a single lung, 3 patients were treated surgically (completion pneumonectomy or cavernostomy) and 1 patient was treated with antifungal therapy alone. Both treatments led to the improved control of CPA. In contrast, patients with CPA in both lungs were not candidates for surgery, and died of CPA. The survival rates after trimodality treatment in the CPA group and the group without CPA were comparable (10-year survival rate, 50.0% vs. 57.6%, P = 0.59). CONCLUSION: The early diagnosis of CPA localized in a single lung after NSCLC surgery is critical to improving control and survival in patients with CPA.

DOI： 10.1007/s00595-020-01960-5

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MAPK Pathway Alterations Correlate with Poor Survival and Drive Resistance to Therapy in Patients with Lung Cancers Driven by ROS1 Fusions. 査読国際誌

Hiroki Sato, Adam J Schoenfeld, Evan Siau, Yue Christine Lu, Huichun Tai, Ken Suzawa, Daisuke Kubota, Allan J W Lui, Besnik Qeriqi, Marissa Mattar, Michael Offin, Masakiyo Sakaguchi, Shinichi Toyooka, Alexander Drilon, Neal X Rosen, Mark G Kris, David Solit, Elisa De Stanchina, Monika A Davare, Gregory J Riely, Marc Ladanyi, Romel Somwar

Clinical cancer research : an official journal of the American Association for Cancer Research 26 ( 12 ) 2932 - 2945 2020年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: ROS1 tyrosine kinase inhibitors (TKI) provide significant benefit in lung adenocarcinoma patients with ROS1 fusions. However, as observed with all targeted therapies, resistance arises. Detecting mechanisms of acquired resistance (AR) is crucial to finding novel therapies and improve patient outcomes. EXPERIMENTAL DESIGN: ROS1 fusions were expressed in HBEC and NIH-3T3 cells either by cDNA overexpression (CD74/ROS1, SLC34A2/ROS1) or CRISPR-Cas9-mediated genomic engineering (EZR/ROS1). We reviewed targeted large-panel sequencing data (using the MSK-IMPACT assay) patients treated with ROS1 TKIs, and genetic alterations hypothesized to confer AR were modeled in these cell lines. RESULTS: Eight of the 75 patients with a ROS1 fusion had a concurrent MAPK pathway alteration and this correlated with shorter overall survival. In addition, the induction of ROS1 fusions stimulated activation of MEK/ERK signaling with minimal effects on AKT signaling, suggesting the importance of the MAPK pathway in driving ROS1 fusion-positive cancers. Of 8 patients, 2 patients harbored novel in-frame deletions in MEK1 (MEK1delE41_L54) and MEKK1 (MEKK1delH907_C916) that were acquired after ROS1 TKIs, and 2 patients harbored NF1 loss-of-function mutations. Expression of MEK1del or MEKK1del, and knockdown of NF1 in ROS1 fusion-positive cells activated MEK/ERK signaling and conferred resistance to ROS1 TKIs. Combined targeting of ROS1 and MEK inhibited growth of cells expressing both ROS1 fusion and MEK1del. CONCLUSIONS: We demonstrate that downstream activation of the MAPK pathway can mediate of innate acquired resistance to ROS1 TKIs and that patients harboring ROS1 fusion and concurrent downstream MAPK pathway alterations have worse survival. Our findings suggest a treatment strategy to target both aberrations.

DOI： 10.1158/1078-0432.CCR-19-3321

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Antitumor Effects of Pan-RAF Inhibitor LY3009120 Against Lung Cancer Cells Harboring Oncogenic BRAF Mutation. 査読国際誌

Shunsaku Miyauchi, Kazuhiko Shien, Tatsuaki Takeda, Kota Araki, Kentaro Nakata, Akihiro Miura, Yuta Takahashi, Eisuke Kurihara, Yusuke Ogoshi, Kei Namba, Ken Suzawa, Hiromasa Yamamoto, Mikio Okazaki, Junichi Soh, Shuta Tomida, Masaomi Yamane, Masakiyo Sakaguchi, Shinichi Toyooka

Anticancer research 40 ( 5 ) 2667 - 2673 2020年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND/AIM: The therapeutic strategy for patients with non-small-cell lung cancer (NSCLC) harboring the BRAF non-V600E mutation has not been established. LY3009120, a newly discovered pan-RAF inhibitor, has shown strong antitumor effects in cancers with various BRAF genotypes. This study investigated the antitumor effects of LY3009120 in NSCLC cells harboring the BRAF non-V600E mutation. MATERIALS AND METHODS: We examined the antitumor effects of LY3009120 by MTS assay and flow cytometry. We analyzed the expression status of proteins by western blot. The mouse xenograft models were used for the in vivo experiments. RESULTS: LY3009120 suppressed BRAF-related downstream pathway molecules and induced cleavage of poly ADP-ribose polymerase in all examined NSCLC cell lines. LY3009120 also inhibited in vivo tumor growth in NSCLC cells harboring the BRAF non-V600E mutation. CONCLUSION: LY3009120 is a potent therapeutic agent for patients with BRAF non-V600E mutant NSCLC.

DOI： 10.21873/anticanres.14237

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YES1 activation induces acquired resistance to neratinib in HER2-amplified breast and lung cancers. 査読国際誌

Tatsuaki Takeda, Hiromasa Yamamoto, Ken Suzawa, Shuta Tomida, Shunsaku Miyauchi, Kota Araki, Kentaro Nakata, Akihiro Miura, Kei Namba, Kazuhiko Shien, Junichi Soh, Tadahiko Shien, Yoshihisa Kitamura, Toshiaki Sendo, Shinichi Toyooka

Cancer science 111 ( 3 ) 849 - 856 2020年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

Molecular-targeted therapies directed against human epidermal growth factor receptor 2 (HER2) are evolving for various cancers. Neratinib is an irreversible pan-HER tyrosine kinase inhibitor and has been approved by the FDA as an effective drug for HER2-positive breast cancer. However, acquired resistance of various cancers to molecular-targeted drugs is an issue of clinical concern, and emergence of resistance to neratinib is also considered inevitable. In this study, we established various types of neratinib-resistant cell lines from HER2-amplified breast and lung cancer cell lines using several drug exposure conditions. We analyzed the mechanisms of emergence of the resistance in these cell lines and explored effective strategies to overcome the resistance. Our results revealed that amplification of YES1, which is a member of the SRC family, was amplified in two neratinib-resistant breast cancer cell lines and one lung cancer cell line. Knockdown of YES1 by siRNA and pharmacological inhibition of YES1 by dasatinib restored the sensitivity of the YES1-amplified cell lines to neratinib in vitro. Combined treatment with dasatinib and neratinib inhibited tumor growth in vivo. This combination also induced downregulation of signaling molecules such as HER2, AKT and MAPK. Our current results indicate that YES1 plays an important role in the emergence of resistance to HER2-targeted drugs, and that dasatinib enables such acquired resistance to neratinib to be overcome.

DOI： 10.1111/cas.14289

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