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• 2014年

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  継続中

  札幌医科大学   フロンティア医学研究所分子医学部門  

• 2011年

  -

  2013年

  札幌医科大学   フロンティア医学研究所遺伝子工学部門  

• 1999年

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  2010年

  札幌医科大学   教育研究機器センター分子医学研究部門  

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  日本生化学会

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  日本癌学会

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  日本薬学会

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• ライフサイエンス   薬系衛生、生物化学  

• ライフサイエンス   薬理学  

• ライフサイエンス   医療薬学  

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• 札幌医科大学   医学部 附属フロンティア医学研究所  

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• 分子生物学

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• Dual inhibition of KIF11 and BCL2L1 induces apoptosis in lung adenocarcinoma cells.

  Yuji Sakuma, Sachie Hirai, Toshiyuki Sumi, Toshiro Niki, Miki Yamaguchi

  Biochemical and biophysical research communications   678   84 - 89  2023年08月  [査読有り]  [国際誌]

  　概要を見る

  EGFR-mutant lung adenocarcinoma (LUAD) mostly depends on EGFR for survival and consequently responds well to EGFR inhibitors. However, resistance to the drugs develops almost universally during treatment. We previously demonstrated that EGFR-mutant LUAD cell lines, HCC827 and H1975, have subpopulations of cells, which we termed HCC827 GR2 and H1975 WR7 cells, that can thrive independently of EGFR signaling. These EGFR-independent EGFR-mutant cancer cells are difficult to treat because they lack sensitivity to EGFR inhibitors. Therefore, the development of novel strategies to target EGFR-independent EGFR-mutant LUAD is particularly important. We found that high expression of kinesin family member 11 (KIF11) correlated with poor survival in patients with LUAD. We also observed that KIF11 silencing caused cell cycle arrest at G2/M in HCC827 GR2 and H1975 WR7 cells. Furthermore, dual silencing of KIF11 plus BCL2L1, an anti-apoptotic BCL2 family member, in these two EGFR-independent sublines resulted in marked apoptosis levels. Dual inhibition of KIF11 plus BCL2L1 also induced apoptosis in HCC827 and H1975 parental cells and a KRAS-mutant LUAD cell line, H441. These findings collectively suggest that dual inhibition of KIF11 plus BCL2L1 may be a new approach for the treatment of LUAD.

  DOI PubMed

• Junctional adhesion molecule 3 is a potential therapeutic target for small cell lung carcinoma.

  Miki Yamaguchi, Sachie Hirai, Masashi Idogawa, Toshiyuki Sumi, Hiroaki Uchida, Naoki Fujitani, Motoko Takahashi, Yuji Sakuma

  Experimental cell research   426 ( 2 ) 113570 - 113570  2023年05月  [査読有り]  [国際誌]

  　概要を見る

  There are few effective therapies for small cell lung carcinoma (SCLC); thus, we need to develop novel and efficacious treatments. We hypothesized that an antibody-drug conjugate (ADC) could be a promising option for SCLC. Several publicly available databases were used to demonstrate the extent to which junctional adhesion molecule 3 (JAM3) mRNA was expressed in SCLC and lung adenocarcinoma cell lines and tissues. Three SCLC cell lines, Lu-135, SBC-5, and Lu-134 A, were selected and examined for JAM3 protein expression by flow cytometry. Finally, we examined the response of the three SCLC cell lines to a conjugate between an anti-JAM3 monoclonal antibody HSL156 (developed in-house) and the recombinant protein DT3C, which consists of diphtheria toxin lacking the receptor-binding domain but containing the C1, C2, and C3 domains of streptococcal protein G. In silico analyses revealed that JAM3 mRNA was expressed higher in SCLC cell lines and tissues than in those of lung adenocarcinoma. As expected, all the three SCLC cell lines examined were positive for JAM3 at the mRNA and protein levels. Consequently, control SCLC cells, but not JAM3-silenced ones, were highly sensitive to HSL156-DT3C conjugates, resulting in dose- and time-dependent decreased viability. Finally, silencing JAM3 alone suppressed the growth of all SCLC cell lines examined. Taken together, these findings suggest that an ADC targeting JAM3 could represent a new approach to treating SCLC patients.

  DOI PubMed

• Dual inhibition of BCL2L1 and MCL1 is highly effective against RET fusion-positive or MET exon 14 skipping mutation-positive lung adenocarcinoma cells.

  Sachie Hirai, Masashi Idogawa, Toshiyuki Sumi, Miki Yamaguchi, Toshiro Niki, Yuji Sakuma

  Biochemical and biophysical research communications   630   24 - 29  2022年11月  [査読有り]  [国際誌]

  担当区分：   筆頭著者

  　概要を見る

  Non-small cell lung carcinomas (NSCLCs), especially lung adenocarcinomas (LUADs), harbor several driver mutations against which highly effective tyrosine kinase inhibitors (TKIs) are available. Although TKIs are generally effective against certain NSCLCs, primary or acquired resistance almost always develops. Driver mutations include RET fusion (∼1-2% of NSCLC cases) and MET exon 14 skipping mutation (METΔex14; ∼3-4%). Surprisingly, the LUAD cell line LC-2/ad with CCDC6-RET fusion thrived independently of RET signaling, and Hs-746T cells harboring METΔex14 plus amplification survived MET silencing. However, these two cell lines were highly sensitive to dual silencing of the representative anti-apoptotic BCL2 family members BCL2L1 and MCL1, undergoing extensive apoptosis in monolayer or 3D on-top culture systems. Moreover, we found that most LUAD cell lines and tissues expressed high levels of BCL2L1 and MCL1 mRNA but extremely low levels of BCL2. Together, these findings suggest that inhibiting BCL2L1 plus MCL1 may represent a new approach to treating LUAD cells irrespective of their driver mutations.

  DOI PubMed

• Anthrax toxin receptor 2 is a potential therapeutic target for non-small cell lung carcinoma with MET exon 14 skipping mutations.

  Miki Yamaguchi, Sachie Hirai, Masashi Idogawa, Hiroaki Uchida, Yuji Sakuma

  Experimental cell research   413 ( 2 ) 113078 - 113078  2022年04月  [査読有り]  [国際誌]

  　概要を見る

  Although MET tyrosine kinase inhibitors (TKIs) are generally effective against non-small cell lung carcinoma (NSCLC) with MET exon 14 skipping mutations (METΔex14), resistance to MET TKIs can occur, indicating the need to develop other therapeutic options. We found that Hs-746 T cells, which harbor METΔex14 plus amplification, were able to survive and grow in the absence of MET signaling, exhibiting primary resistance to MET TKIs. We also found a moderately positive correlation between MET and anthrax toxin receptor 2 (ANTXR2) mRNA expression in NSCLC cell lines using data from the Cancer Dependency Map database. As expected, Hs-746 T cells were positive for ANTXR2 expression. We used an antibody-drug conjugate (ADC) analog in the form of an anti-ANTXR2 monoclonal antibody, H8R23, conjugated to DT3C recombinant protein which consists of diphtheria toxin (DT) lacking the receptor-binding domain but containing the C1, C2, and C3 domains of streptococcal protein G (3C). H8R23-DT3C conjugates, which function in vitro like an ADC, induced Hs-746 T cells to undergo apoptosis, resulting in decreased viability. These findings collectively suggest that an ADC targeting ANTXR2 could be effective for the treatment of METΔex14-positive NSCLC.

  DOI PubMed

• MCL1 inhibition enhances the efficacy of docetaxel against airway-derived squamous cell carcinoma cells.

  Yuji Sakuma, Sachie Hirai, Toshiyuki Sumi, Makoto Tada, Takashi Kojima, Toshiro Niki, Miki Yamaguchi

  Experimental cell research   406 ( 2 ) 112763 - 112763  2021年09月  [査読有り]  [国際誌]

  　概要を見る

  MCL1 is an anti-apoptotic BCL2 family member that is often overexpressed in various malignant tumors. However, few reports have described the role of MCL1 in squamous cell carcinoma (SqCC) derived from airways including the lung. In this study, we examined whether MCL1 could be a novel druggable target for airway-derived SqCC, for which effective molecular targeted drugs are unavailable. We searched the Kaplan-Meier Plotter database and found that high MCL1 mRNA expression was significantly associated with shorter survival in patients with lower airway (lung) or upper airway (head and neck) derived SqCC. We also explored the Expression Atlas database and learned that authentic lung SqCC cell lines expressing both TP63 and KRT5 mRNA were extremely sparse among the publicly available "lung SqCC cell lines", with an exception being HARA cells. HARA cells were highly dependent on MCL1 for survival, and MCL1-depleted cells were not able to grow, and even declined in number, upon docetaxel (DTX) exposure in vitro and in vivo. Similar in vitro experimental findings, including those in a 3D culture model, were also obtained using Detroit 562 pharyngeal SqCC cells. These findings suggested that combined treatment with MCL1 silencing plus DTX appears highly effective against airway-derived SqCC.

  DOI PubMed

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• Kras変異陽性肺腺癌におけるsurvivinを標的とした治療戦略

  角 俊行, 田中 悠祐, 多田 周, 平井 幸恵, 山口 美樹, 山田 玄, 渡辺 敦, 高橋 弘毅, 佐久間 裕司

  日本呼吸器学会誌 ( (一社)日本呼吸器学会 )  7 ( 増刊 ) 210 - 210  2018年03月

• ヒト末梢気道幹細胞の研究

  田中 悠祐, 角 俊行, 多田 周, 山口 美樹, 平井 幸恵, 渡辺 敦, 高橋 弘毅, 佐久間 裕司

  日本呼吸器学会誌 ( (一社)日本呼吸器学会 )  7 ( 増刊 ) 153 - 153  2018年03月

• KRAS変異陽性肺腺癌におけるMCL1の治療標的分子としての基礎的検討

  多田周, 角俊行, 田中悠祐, 平井幸恵, 山口美樹, 高橋有毅, 鶴田航大, 槙龍之輔, 三品泰二郎, 宮島正博, 渡辺敦, 佐久間裕司

  日本呼吸器外科学会総会(Web)   35th  2018年

  J-GLOBAL

• KRAS変異陽性肺腺癌におけるMCL1は治療標的分子となりえるか

  多田周, 角俊行, 田中悠祐, 平井幸恵, 山口美樹, 高橋有毅, 鶴田航大, 槙龍之輔, 三品泰二郎, 宮島正博, 渡辺毅, 佐久間裕司

  日本肺癌学会総会号   59th  2018年

  J-GLOBAL

• KRAS変異陽性肺腺癌におけるMEK阻害薬trametinibとsurvivinの関連について

  角 俊行, 田中 悠祐, 多田 周, 平井 幸恵, 山口 美樹, 佐久間 裕司, 山田 玄, 高橋 弘毅, 渡辺 敦

  肺癌 ( (NPO)日本肺癌学会 )  57 ( 7 ) 918 - 918  2017年12月

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• 高性能イミュノトキシンを用いた急性骨髄性白血病の標的化治療

  基盤研究(C)

  研究期間:

  2011年

  -

  2013年

   

  山口 美樹, 濱田 洋文, 平井 幸恵, 内田 宏昭

  　研究概要を見る

  私たちはジフテリア毒素(DT)とプロテインG(3C)を含むリコンビナントタンパクであるDT3Cを開発した。DT3Cとモノクローナル抗体(MoAb)の結合は容易でありMoAb-DT3C結合体は表面抗原に結合し細胞内へ移行することで殺細胞効果を示す。この系を応用した選択法で腫瘍細胞に特異的なMoAbの樹立が可能であり、私たちは224個のMoAbを樹立した。これらのMoAbはいずれも高いイミュノトキシン活性を示し、抗体薬候補分子に対する抗体が多く含まれていた。また、現在標的治療薬として開発中の抗体が多く含まれており、この方法が抗体薬物複合体(ADC)治療に有効な抗体の選別法であることが示された。