北井　秀典 (キタイ　ヒデノリ)

医学研究院　内科系部門　内科学分野助教
北海道大学病院助教
Last Updated :2024/12/06

■研究者基本情報

学位

  • 医学博士, 北海道大学, 2017年12月

Researchmap個人ページ

ホームページURL

研究者番号

  • 30975412

ORCID ID

J-Global ID

研究分野

  • ライフサイエンス, 呼吸器内科学
  • ライフサイエンス, 腫瘍診断、治療学

■研究活動情報

受賞

  • 2018年, 上原記念財団海外留学助成リサーチフェローシップ　　　　　　　　　　　　　　　

論文

  • 80歳以上の高齢者に対する経気管支生検の安全性と有用性の検討　　　　　　　　　　　　　　　
    畠山 酉季, 高島 雄太, 鈴木 孝敏, 棟方 奈菜, 中村 友彦, 高橋 宏典, 古田 恵, 北井 秀典, 庄司 哲明, 朝比奈 肇, 菊地 英毅, 菊地 順子, 榊原 純, 品川 尚文, 今野 哲
    気管支学, 45, 6, 444, 444, (一社)日本呼吸器内視鏡学会, 2023年11月
    日本語
  • Inhibition of non-homologous end joining mitigates paclitaxel resistance resulting from mitotic slippage in non-small cell lung cancer.
    Kosuke Tsuji, Eiki Kikuchi, Yuta Takashima, Tetsuaki Shoji, Hirofumi Takahashi, Shotaro Ito, Daisuke Morinaga, Masahiro Kashima, Makie Maeda, Hidenori Kitai, Junko Kikuchi, Jun Sakakibara-Konishi, Satoshi Konno
    Cell cycle (Georgetown, Tex.), 1, 11, 2023年08月17日, ［国際誌］
    英語, 研究論文（学術雑誌）, Mitotic slippage, which enables cancer cells to bypass cell death by transitioning from mitosis to the G1 phase without undergoing normal cytokinesis, is one likely mechanism of paclitaxel (PTX) resistance. DNA double-strand breaks (DSBs) in the G1 phase are mainly repaired through non-homologous end joining (NHEJ). Therefore, inhibiting NHEJ could augment the PTX-induced cytotoxicity by impeding the repair of PTX-induced DSBs during the G1 phase following mitotic slippage. We aimed to evaluate the effects of NHEJ inhibition on mitotic slippage after PTX treatment in non-small cell lung cancer (NSCLC). H1299, A549, H1975, and H520 NSCLC cell lines were employed. In addition, A-196 and JQ1 were used as NHEJ inhibitors. H1299 cells were PTX-resistant and exhibited an increased frequency of mitotic slippage upon PTX treatment. NHEJ inhibitors significantly augmented the PTX-induced cytotoxicity, DSBs, and apoptosis in H1299 cells. The newly generated PTX-resistant cells were even more prone to mitotic slippage following PTX treatment and susceptible to the combined therapy. Docetaxel further demonstrated synergistic effects with the NHEJ inhibitor in PTX-resistant cells. NHEJ inhibition may overcome intrinsic or acquired PTX resistance resulting from mitotic slippage by synergistically increasing the cytotoxic effects of antimitotic drugs in NSCLC.
  • 80歳以上の高齢者に対する経気管支生検の安全性と有用性の検討
    畠山 酉季, 高島 雄太, 鈴木 孝敏, 棟方 奈菜, 中村 友彦, 高橋 宏典, 古田 恵, 北井 秀典, 庄司 哲明, 朝比奈 肇, 菊地 英毅, 菊地 順子, 榊原 純, 品川 尚文, 今野 哲
    気管支学, 45, Suppl., S217, S217, (一社)日本呼吸器内視鏡学会, 2023年06月
    日本語
  • WEE1 inhibition enhances the antitumor immune response to PD-L1 blockade by the concomitant activation of STING and STAT1 pathways in SCLC
    Hirokazu Taniguchi, Rebecca Caeser, Shweta S. Chavan, Yingqian A. Zhan, Andrew Chow, Parvathy Manoj, Fathema Uddin, Hidenori Kitai, Rui Qu, Omar Hayatt, Nisargbhai S. Shah, Álvaro Quintanal Villalonga, Viola Allaj, Evelyn M. Nguyen, Joseph Chan, Adam O. Michel, Hiroshi Mukae, Elisa de Stanchina, Charles M. Rudin, Triparna Sen
    Cell Reports, 2022年05月
    研究論文（学術雑誌）
  • Response to First-Line Osimertinib Treatment in Non–Small-Cell Lung Cancer With Coexisting G719A and Primary T790M Epidermal Growth Factor Receptor Mutations
    Ikari, T., Sakakibara-Konishi, J., Yamamoto, G., Kitai, H., Mizugaki, H., Asahina, H., Kikuchi, E., Shinagawa, N.
    Clinical Lung Cancer, 20, 4, 2019年
    研究論文（学術雑誌）
  • Response to Crizotinib Re-administration After Progression on Lorlatinib in a Patient With ALK-rearranged Non–small-cell Lung Cancer
    Sakakibara-Konishi, J., Kitai, H., Ikezawa, Y., Hatanaka, Y., Sasaki, T., Yoshida, R., Chiba, S., Matsumoto, S., Goto, K., Mizugaki, H., Shinagawa, N.
    Clinical Lung Cancer, 20, 5, 2019年
    研究論文（学術雑誌）
  • Response of BRAF V600E -Mutant Lung Adenocarcinoma With Brain Metastasis and Leptomeningeal Dissemination to Dabrafenib Plus Trametinib Treatment
    Yamamoto, G., Sakakibara-Konishi, J., Ikari, T., Kitai, H., Mizugaki, H., Asahina, H., Kikuchi, E., Shinagawa, N.
    Journal of Thoracic Oncology, 14, 5, 2019年
    研究論文（学術雑誌）
  • A clinical analysis of 10 cases with oligometastases of non-small cell carcinoma
    Kunisaki, M., Sakakibara, J., Kikuchi, H., Kitai, H., Mizugaki, H., Asahina, H., Kikuchi, E., Shinagawa, N., Nishimura, M.
    Japanese Journal of Lung Cancer, 58, 7, 2018年
    研究論文（学術雑誌）
  • Distinct dependencies on receptor tyrosine kinases in the regulation of MAPK signaling between BRAF V600E and non-V600E mutant lung cancers
    Kotani, H., Adachi, Y., Kitai, H., Tomida, S., Bando, H., Faber, A.C., Yoshino, T., Voon, D.C., Yano, S., Ebi, H.
    Oncogene, 37, 13, 2018年
    研究論文（学術雑誌）, BRAF is one of the most frequently mutated genes across a number of different cancers, with the best-characterized mutation being V600E. Despite the successes of treating BRAF mutant V600E lung cancer with BRAF pathway inhibitors, treatment strategies targeting tumors with non-V600E mutations are yet to be established. We studied cellular signaling differences between lung cancers with different BRAF mutations and determined their sensitivities to BRAF pathway inhibitors. Here, we observed that MEK inhibition induced feedback activation of the receptor tyrosine kinase (RTK) EGFR, and in some cases the RTK FGFR, resulting in transient suppression of ERK phosphorylation in BRAF non-V600E, but not BRAF V600E, mutant cells. Furthermore, we found that both EGFR and FGFR activated the MEK/ERK pathway, despite the presence of BRAF non-V600E mutations with elevated kinase activity. Moreover, in BRAF non-V600E mutants with impaired kinase activities, EGFR had even greater control over the MEK/ERK pathway, essentially contributing completely to the tonic mitogen-activated protein kinase (MAPK) signal. Accordingly, the combination of MEK inhibitor with EGFR inhibitor was effective at shrinking tumors in mouse model of BRAF non-V600E mutant lung cancer. Furthermore, the results were recapitulated with a clinically relevant dual inhibitor of EGFR and RAF, BGB-283. Overall, although BRAF V600E mutant cells are sensitive to BRAF inhibition, non-V600E mutant cancer cells are reliant on RTKs for their MAPK activation and inhibiting both MEK and RTKs are necessary in these cancers. Our findings provide evidence of critical survival signals in BRAF non-V600E mutant cancers, which could pave the way for effective treatment of these cancers.
  • Epithelial-to-mesenchymal transition antagonizes response to targeted therapies in lung cancer by suppressing BIM
    Song, K.-A., Niederst, M.J., Lochmann, T.L., Hata, A.N., Kitai, H., Ham, J., Floros, K.V., Hicks, M.A., Hu, H., Mulvey, H.E., Drier, Y., Heisey, D.A.R., Hughes, M.T., Patel, N.U., Lockerman, E.L., Garcia, A., Gillepsie, S., Archibald, H.L., Gomez-Caraballo, M., Nulton, T.J., Windle, B.E., Piotrowska, Z., Sahingur, S.E., Taylor, S.M., Dozmorov, M., Sequist, L.V., Bernstein, B., Ebi, H., Engelman, J.A., Faber, A.C.
    Clinical Cancer Research, 24, 1, 2018年
    研究論文（学術雑誌）, Purpose: Epithelial-to-mesenchymal transition (EMT) confers resistance to a number of targeted therapies and chemotherapies. However, it has been unclear why EMT promotes resistance, thereby impairing progress to overcome it.Experimental Design: We have developed several models of EMT-mediated resistance to EGFR inhibitors (EGFRi) in EGFR-mutant lung cancers to evaluate a novel mechanism of EMT-mediated resistance.Results: We observed that mesenchymal EGFR-mutant lung cancers are resistant to EGFRi-induced apoptosis via insufficient expression of BIM, preventing cell death despite potent suppression of oncogenic signaling following EGFRi treatment. Mechanistically, we observed that the EMT transcription factor ZEB1 inhibits BIM expression by binding directly to the BIM promoter and repressing transcription. Derepression of BIM expression by depletion of ZEB1 or treatment with the BH3 mimetic ABT-263 to enhance "free" cellular BIM levels both led to resensitization of mesenchymal EGFR-mutant cancers to EGFRi. This relationship between EMT and loss of BIM is not restricted to EGFR-mutant lung cancers, as it was also observed in KRAS-mutant lung cancers and large datasets, including different cancer subtypes.Conclusions: Altogether, these data reveal a novel mechanistic link between EMT and resistance to lung cancer targeted therapies. Clin Cancer Res; 24(1); 197-208. ©2017 AACR.
  • Improvements of visual function and outer retinal morphology following spontaneous regression of cancer in anti-recoverin cancer-associated retinopathy
    Suimon, Y., Saito, W., Hirooka, K., Kanda, A., Kitai, H., Sakakibara-Konishi, J., Ishida, S.
    American Journal of Ophthalmology Case Reports, 5, 137, 140, 2017年, ［国際誌］
    英語, 研究論文（学術雑誌）, PURPOSE: To report an anti-recoverin antibody-positive cancer-associated retinopathy (anti-recoverin CAR) patient with remarkable improvements of visual function and outer retinal morphology following spontaneous regression of cancer. OBSERVATIONS: A 65-year-old woman with small cell lung carcinoma developed progressive, bilateral vision loss with diffuse loss of the ellipsoid zone at the macula on optical coherence tomography and marked reduced responses of a- and b-waves on electroretinography. Western blot analysis led to a diagnosis of anti-recoverin CAR. The visual function and outer retinal morphology gradually improved following spontaneous regression of the cancer and the initiation of systemic corticosteroid. Subsequent intermittent chemotherapy and continuation of corticosteroid maintained reduction of the cancer and prevented the recurrence of CAR, with preservation of improvements of the visual function and macular outer retinal morphology. CONCLUSIONS AND IMPORTANCE: These results suggest that requirement for obtaining good visual prognosis in CAR patients is to make the cancer regress prior to falling into photoreceptor apotosis.
  • Key roles of EMT for adaptive resistance to MEK inhibitor in KRAS mutant lung cancer
    Kitai, H., Ebi, H.
    Small GTPases, 8, 3, 2017年
    研究論文（学術雑誌）
  • Resistance mediated by alternative receptor tyrosine kinases in FGFR1-amplified lung cancer
    Adachi, Y., Watanabe, K., Kita, K., Kitai, H., Kotani, H., Sato, Y., Inase, N., Yano, S., Ebi, H.
    Carcinogenesis, 38, 11, 2017年
    研究論文（学術雑誌）, Fibroblast growth factor receptor 1 (FGFR1) amplification has been identified in 10-20% of patients with squamous non-small-cell lung cancer. Preclinical models showed promising activity of specific FGFR inhibitors, but early clinical trials showed that only a small fraction of patients with FGFR1-amplified lung cancer responded to FGFR inhibitors. These unsatisfactory results were partly explained by heterogeneous amplicons around the 8p11 genomic region, leading to false-positive amplification results. Furthermore, discrepancies in the gene amplification and protein expression of FGFR1 were also reported. In this study, we identified the roles of alternative receptor tyrosine kinases (RTKs) in FGFR1-amplified lung cancer. These alternative RTKs dominantly activate phosphoinositide 3-kinase-AKT signaling and also mitigate sustained inhibition of mitogen-activated protein kinase signaling by FGFR inhibitors. The rebound activation of extracellular signal-regulated kinase phosphorylation was associated with sensitivity to the drugs. Combinatorial inhibition of alternative RTKs and FGFR1 was required to suppress both AKT and extracellular signal-regulated kinase phosphorylation and to induce key pro-apoptotic proteins BIM and p53 upregulated modulator of apoptosis (PUMA). Furthermore, even in FGFR inhibitor-sensitive NCI-H1581 lung cancer cells, MET-expressing clones were already detectable at a very low frequency before resistance induction. Selection of these pre-existing subclones resulted in FGFR inhibitor resistance because of the activation of AKT and extracellular signal-regulated kinase by MET signaling that was mediated by GRB2 associated binding protein 1 (GAB1). These results suggest that incomplete suppression of key survival signals led to intrinsic and acquired resistance to FGFR inhibitors. Our results may help explain the low clinical response rates to FGFR inhibitors in FGFR1-amplified lung cancer.
  • Epithelial-to-mesenchymal transition defines feedback activation of receptor tyrosine kinase signaling induced by MEK inhibition in KRAS-mutant lung cancer
    Kitai, H., Ebi, H., Tomida, S., Floros, K.V., Kotani, H., Adachi, Y., Oizumi, S., Nishimura, M., Faber, A.C., Yano, S.
    Cancer Discovery, 6, 7, 2016年
    研究論文（学術雑誌）,

    Unlabelled

    KRAS is frequently mutated in lung cancer. Whereas MAPK is a well-known effector pathway of KRAS, blocking this pathway with clinically available MAPK inhibitors is relatively ineffective. Here, we report that epithelial-to-mesenchymal transition rewires the expression of receptor tyrosine kinases, leading to differential feedback activation of the MAPK pathway following MEK inhibition. In epithelial-like KRAS-mutant lung cancers, this feedback was attributed to ERBB3-mediated activation of MEK and AKT. In contrast, in mesenchymal-like KRAS-mutant lung cancers, FGFR1 was dominantly expressed but suppressed by the negative regulator Sprouty proteins; MEK inhibition led to repression of SPRY4 and subsequent FGFR1-mediated reactivation of MEK and AKT. Therapeutically, the combination of a MEK inhibitor (MEKi) and an FGFR inhibitor (FGFRi) induced cell death in vitro and tumor regressions in vivo These data establish the rationale and a therapeutic approach to treat mesenchymal-like KRAS-mutant lung cancers effectively with clinically available FGFR1 and MAPK inhibitors.

    Significance

    Adaptive resistance to MEKi is driven by receptor tyrosine kinases specific to the differentiation state of the KRAS-mutant non-small cell lung cancer (NSCLC). In mesenchymal-like KRAS-mutant NSCLC, FGFR1 is highly expressed, and MEK inhibition relieves feedback suppression of FGFR1, resulting in reactivation of ERK; suppression of ERK by MEKi/FGFRi combination results in tumor shrinkage. Cancer Discov; 6(7); 754-69. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 681.
  • Co-active receptor tyrosine kinases mitigate the effect of FGFR inhibitors in FGFR1-amplified lung cancers with low FGFR1 protein expression
    Kotani, H., Ebi, H., Kitai, H., Nanjo, S., Kita, K., Huynh, T.G., Ooi, A., Faber, A.C., Mino-Kenudson, M., Yano, S.
    Oncogene, 35, 27, 2016年
    研究論文（学術雑誌）, Targeted therapies are effective in subsets of lung cancers with EGFR mutations and anaplastic lymphoma kinase (ALK) translocations. Large-scale genomics have recently expanded the lung cancer landscape with FGFR1 amplification found in 10-20% of squamous cell carcinomas (SCCs). However, the response rates have been low for biomarker-directed fibroblast growth factor receptor (FGFR) inhibitor therapy in SCC, which contrasts to the relatively high rates of response seen in EGFR mutant and ALK-translocated lung cancers treated with epidermal growth factor receptor (EGFR) inhibitors and ALK inhibitors, respectively. In order to better understand the low response rates of FGFR1-amplified lung cancers to FGFR inhibitors, relationships between gene copy number, mRNA expression and protein expression of FGFR1 were assessed in cell lines, tumor specimens and data from The Cancer Genome Atlas. The importance of these factors for the sensitivity to FGFR inhibitors was determined by analyzing drug screen data and conducting in vitro and in vivo experiments. We report that there was a discrepancy between FGFR1 amplification level and FGFR1 protein expression in a number of these cell lines, and the cancers with unexpectedly low FGFR1 expression were uniformly resistant to the different FGFR inhibitors. Further interrogation of the receptor tyrosine kinase activity in these discordant cell lines revealed co-activation of HER2 and platelet-derived growth factor receptor-α (PDGFRα) caused by gene amplification or ligand overexpression maintained phosphoinositide 3-kinase (PI3K) and MEK/ERK signaling even in the presence of FGFR inhibitor. Accordingly, co-inhibition of FGFR1 and HER2 or PDGFRα led to enhanced drug responses. In contrast, FGFR1-amplified high FGFR1 protein-expressing lung cancers are sensitive to FGFR inhibitor monotherapy by downregulating ERK signaling. Addition of a PI3K inhibitor to these high FGFR1 protein-expressing cancers further sensitized them to FGFR inhibitor. These data reveal that biomarker-directed trials for FGFR1-amplified SCC require assessment of FGFR1 protein expression and uncover novel therapeutic strategies for FGFR1-amplified SCC with low FGFR1 protein expression.

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