Terai, Hideki



School of Medicine, Department of Internal Medicine (Pulmonary Medicine) (Shinanomachi)


Senior Assistant Professor (Non-tenured)/Assistant Professor (Non-tenured)


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  • IGF2 Autocrine-mediated IGF1R activation is a clinically relevant mechanism of osimertinib resistance in Lung Cancer

    Manabe T., Yasuda H., Terai H., Kagiwa H.D.A., Hamamoto J., Ebisudani T., Kobayashi K., Masuzawa K., Ikemura S., Kawa I.D.A., Hayashi Y., Fukui K., Horimoto K., Fukunaga K., Soeji K.M.A.

    Molecular Cancer Research (Molecular Cancer Research)  18 ( 4 ) 549 - 559 2020.04

    ISSN  15417786

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    © 2020 American Association for Cancer Research. EGFR-mutated lung cancer accounts for a significant proportion of lung cancer cases worldwide. For these cases, osimertinib, a thirdgeneration EGFR tyrosine kinase inhibitor, is extensively used as a first-line or second-line treatment. However, lung cancer cells acquire resistance to osimertinib in 1 to 2 years. Thus, a thorough clarification of resistance mechanisms to osimertinib is highly anticipated. Recent next-generation sequencing (NGS) of lung cancer samples identified several genetically defined resistance mechanisms to osimertinib, such as EGFR C797S or MET amplification. However, nongenetically defined mechanisms are not well evaluated. For a thorough clarification of osimertinib resistance, both genetic and nongenetic mechanisms are essential. By using our comprehensive protein phosphorylation array, we detected IGF1R bypass pathway activation after EGFR abolishment. Both of our established lung cancer cells and patient-derived lung cancer cells demonstrated IGF2 autocrine-mediated IGF1R pathway activation as a mechanism of osimertinib resistance. Notably, this resistance mechanism was not detected by a previously performed NGS, highlighting the essential roles of living cancer cells for a thorough clarification of resistance mechanisms. Interestingly, the immunohistochemical analysis confirmed the increased IGF2 expression in lung cancer patients who were treated with osimertinib and met the established clinical definition of acquired resistance. The findings highlight the crucial roles of cell-Autonomous ligand expression in osimertinib resistance. Here, we report for the first time the IGF2 autocrine-mediated IGF1R activation as a nongenetic mechanism of osimertinib resistance in lung cancer at a clinically relevant level.

  • A phase II trial of induction of erlotinib followed by cytotoxic chemotherapy for EGFR mutation-positive non-squamous non-small cell lung cancer patients

    Tani T., Naoki K., Yasuda H., Arai D., Ishioka K., Ohgino K., Yoda S., Nakayama S., Satomi R., Terai H., Ikemura S., Sato T., Soejima K.

    Cancer Chemotherapy and Pharmacology (Cancer Chemotherapy and Pharmacology)  84 ( 5 ) 1065 - 1071 2019.11

    ISSN  03445704

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    © 2019, Springer-Verlag GmbH Germany, part of Springer Nature. Background: No consensus has been reached regarding the treatment order and timing of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and cytotoxic chemotherapy administration for EGFR mutation-positive non-small cell lung cancer (NSCLC) patients. Methods: In this phase II trial, chemotherapy-naïve patients harboring activating EGFR mutations with stage IIIB/IV or post-surgical recurrent non-squamous NSCLC were enrolled. Patients were treated with erlotinib induction at 150 mg/day for 3 months. This was followed by cytotoxic chemotherapy with platinum plus pemetrexed, with or without bevacizumab, when the induction erlotinib achieved a CR or PR. The primary end point was the 1-year progression-free survival (PFS) rate, while the secondary end points were the response rate (RR), PFS, safety, and overall survival (OS). Results: Twenty patients were enrolled in this study. The median age was 63 years. Eighteen patients had stage IV disease, and 2 patients had recurrent disease. Eleven patients achieved a PR after induction of erlotinib and 9 out of 11 patients were switched to chemotherapy. The 1-year PFS rate was 45.0% (90% CI 26.8–63.2), the overall RR was 55.0%, and the median PFS was 10.7 months in the intention-to-treat (ITT) population. Grade 3–4 adverse events were reported for 40% of the patients, including patients with leukopenia (10%), neutropenia (20%), and interstitial pneumonitis, bacterial pneumonia, rash, and nausea (all 5%). Conclusions: The primary end point of this study was not achieved. However, the therapy was well tolerated and may be a treatment option for a future study with patients responsive to short-term erlotinib treatment. Clinical trials registration number: UMIN ID: 000013125.

  • Efficacy of afatinib or osimertinib plus cetuximab combination therapy for non-small-cell lung cancer with EGFR exon 20 insertion mutations

    Hasegawa H., Yasuda H., Hamamoto J., Masuzawa K., Tani T., Nukaga S., Hirano T., Kobayashi K., Manabe T., Terai H., Ikemura S., Kawada I., Naoki K., Soejima K.

    Lung Cancer (Lung Cancer)  127   146 - 152 2019.01

    ISSN  01695002

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    © 2018 Elsevier B.V. Objectives: Epidermal growth factor receptor (EGFR) mutation-positive lung cancer accounts for a significant subgroup of non-small cell lung cancers (NSCLC). Approximately 4–10% of EGFR mutations in NSCLC are EGFR exon 20 insertion mutations, which are reportedly associated with resistance to EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment. NSCLC patients carrying these mutations are rarely treated with EGFR-TKIs. The purpose of this study was to evaluate the efficacy of afatinib or osimertinib plus cetuximab combination therapy in experimental NSCLC models with EGFR exon 20 insertion mutations. Materials and methods: The EGFR mutations examined in this study were A763_Y764insFQEA, Y764_V765insHH, A767_V769dupASV, and D770_N771insNPG. Ba/F3 cells constitutively expressing wild type or mutated EGFR were used to determine the efficacy of afatinib or osimertinib plus cetuximab combination therapy in vitro. To determine the efficacy of the combination therapy in vivo, female BALB/c-nu mice were injected subcutaneously with 1 million Ba/F3 cells carrying EGFR A767_V769dupASV or Y764_V765insHH. Results: We observed a mild but significant (P < 0.05) additive effect of the combination therapy against several EGFR exon 20 insertion mutations in vitro. Regarding EGFR A767_V769dupASV and EGFR Y764_V765insHH, cetuximab and afatinib single treatment did not induce significant inhibition of tumor formation; however, afatinib plus cetuximab combination treatment induced significant (P < 0.05) tumor growth inhibition without significant body weight loss or skin rash. Conclusion: The combination therapy induced a more potent inhibitory effect against several EGFR exon 20 insertion mutations than either therapy alone. Cetuximab can potentially increase the efficacy of afatinib or osimertinib in NSCLC with EGFR exon 20 insertion mutations.

  • Monomer preference of EGFR tyrosine kinase inhibitors influences the synergistic efficacy of combination therapy with cetuximab

    Oashi A., Yasuda H., Kobayashi K., Tani T., Hamamoto J., Masuzawa K., Manabe T., Terai H., Ikemura S., Kawada I., Naoki K., Soejima K.

    Molecular Cancer Therapeutics (Molecular Cancer Therapeutics)  18 ( 9 ) 1593 - 1601 2019

    ISSN  15357163

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    © 2019 American Association for Cancer Research. EGFR-mutated lung cancer is a significant subgroup of non–small cell lung cancer. To inhibit EGFR-mediated signals, multiple EGFR tyrosine kinase inhibitors (EGFR-TKI) have been developed; however, approximately one third of patients with EGFR-mutated lung cancer do not respond to EGFR-TKIs. More effective inhibition of EGFR-mediated signals is therefore necessary. For cancers expressing mutated EGFR, including EGFR T790M, which confers resistance to first- (gefitinib and erlotinib) and second- (afatinib) generation EGFR-TKIs, the synergistic efficacy of afatinib and cetuximab combination therapy has been reported in preclinical and clinical studies; however, the mechanisms underlying this effect remain elusive. In this study, we evaluated the effects of multiple EGFR-TKIs on the EGFR monomer–dimer equilibrium by inducing dimerization-impairing mutations in cells expressing EGFR. Interestingly, we found that afatinib and dacomitinib exhibit a monomer preference: cells expressing dimerization-impaired EGFR mutants exhibited increased sensitivity to afatinib and dacomitinib relative to those with dimerization-competent EGFR mutants. Although EGFR-TKIs themselves induce dimerization of EGFR, the inhibition of dimerization by cetuximab overcame EGFR-TKI–induced dimerization. By shifting the monomer–dimer equilibrium toward monomer dominance using cetuximab, the effectiveness of afatinib and dacomitinib improved significantly. We report a novel and clinically relevant phenomenon, the monomer preference of EGFR-TKIs, which can explain the mechanism underlying the synergism observed in afatinib and cetuximab combination therapy. In addition, we propose the novel concept that monomer–dimer equilibrium is an important factor in determining EGFR-TKI efficacy. These findings provide novel insights into treatment strategies for EGFR-TKI–refractory non–small cell lung cancer.

  • Overcoming Resistance to Dual Innate Immune and MEK Inhibition Downstream of KRAS

    Kitajima S., Asahina H., Chen T., Guo S., Quiceno L., Cavanaugh J., Merlino A., Tange S., Terai H., Kim J., Wang X., Zhou S., Xu M., Wang S., Zhu Z., Thai T., Takahashi C., Wang Y., Neve R., Stinson S., Tamayo P., Watanabe H., Kirschmeier P., Wong K., Barbie D.

    Cancer Cell (Cancer Cell)  34 ( 3 ) 439 - 452.e6 2018.09

    ISSN  15356108

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    © 2018 Elsevier Inc. Despite extensive efforts, oncogenic KRAS remains resistant to targeted therapy. Combined downstream RAL-TBK1 and MEK inhibition induces only transient lung tumor shrinkage in KRAS-driven genetically engineered mouse models (GEMMs). Using the sensitive KRAS;LKB1 (KL) mutant background, we identify YAP1 upregulation and a therapy-induced secretome as mediators of acquired resistance. This program is reversible, associated with H3K27 promoter acetylation, and suppressed by BET inhibition, resensitizing resistant KL cells to TBK1/MEK inhibition. Constitutive YAP1 signaling promotes intrinsic resistance in KRAS;TP53 (KP) mutant lung cancer. Intermittent treatment with the BET inhibitor JQ1 thus overcomes resistance to combined pathway inhibition in KL and KP GEMMs. Using potent and selective TBK1 and BET inhibitors we further develop an effective therapeutic strategy with potential translatability to the clinic. Kitajima et al. identify BET-regulated YAP1 upregulation as a mediator of acquired and intrinsic resistance in KRAS;LKB1 and KRAS;TP53 mutant lung cancer cells, respectively, to combined TBK1 and MEK inhibition and show that intermittent BET inhibition overcomes this resistance.

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  • Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses

    Cañadas I., Thummalapalli R., Kim J., Kitajima S., Jenkins R., Christensen C., Campisi M., Kuang Y., Zhang Y., Gjini E., Zhang G., Tian T., Sen D., Miao D., Imamura Y., Thai T., Piel B., Terai H., Aref A., Hagan T., Koyama S., Watanabe M., Baba H., Adeni A., Lydon C., Tamayo P., Wei Z., Herlyn M., Barbie T., Uppaluri R., Sholl L., Sicinska E., Sands J., Rodig S., Wong K., Paweletz C., Watanabe H., Barbie D.

    Nature Medicine (Nature Medicine)  24 ( 8 ) 1143 - 1150 2018.08

    ISSN  10788956

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    © 2018, The Author(s). Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance 1–4 . This phenomenon has been implicated in chemorefractory small cell lung cancer and resistance to targeted therapies 5–8 , but remains incompletely defined. Here, we identify a subclass of endogenous retroviruses (ERVs) that engages innate immune signaling in these cells. Stimulated 3 prime antisense retroviral coding sequences (SPARCS) are oriented inversely in 3′ untranslated regions of specific genes enriched for regulation by STAT1 and EZH2. Derepression of these loci results in double-stranded RNA generation following IFN-γ exposure due to bi-directional transcription from the STAT1-activated gene promoter and the 5′ long terminal repeat of the antisense ERV. Engagement of MAVS and STING activates downstream TBK1, IRF3, and STAT1 signaling, sustaining a positive feedback loop. SPARCS induction in human tumors is tightly associated with major histocompatibility complex class 1 expression, mesenchymal markers, and downregulation of chromatin modifying enzymes, including EZH2. Analysis of cell lines with high inducible SPARCS expression reveals strong association with an AXL/MET-positive mesenchymal cell state. While SPARCS-high tumors are immune infiltrated, they also exhibit multiple features of an immune-suppressed microenviroment. Together, these data unveil a subclass of ERVs whose derepression triggers pathologic innate immune signaling in cancer, with important implications for cancer immunotherapy.