Development of a curative treatment strategy for lung cancer using the persister cancer cell mouse model.

• Project/Area Number: 19K08625
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Okayama University
• Principal Investigator: Ohashi Kadoaki 岡山大学, 大学病院, 研究准教授 (60729193)
• Co-Investigator(Kenkyū-buntansha): 木浦 勝行 岡山大学, 大学病院, 教授 (10243502)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 非小細胞肺癌 / EGFR変異 / 腫瘍免疫 / PD-1 / VEGR2 / 肺癌 / 非小細胞癌 / persister / persisterがん細胞 / 遺伝子改変マウス

Outline of Research at the Start

EGFR変異を伴う肺癌は、日本人の非喫煙者に発生する肺癌の半数以上を占める重要な疾患である。EGFRチロシンキナーゼ阻害薬（TKI）は、高い効果を示すが、完全寛解、根治しないことが未解決の課題である。「persister」がん細胞（しつこく生き残る耐性細胞）と呼ばれる細胞集団が、完全寛解、根治に向けた新規の治療標的として注目されている。
本研究は、EGFR遺伝子改変肺癌マウスモデルを用い、1)「persister」がん細胞およびその腫瘍微小環境を評価、検証し治療標的を同定、またマウスモデルで「persister」がん細胞の阻害効果を検証し、肺癌根絶を目標とした臨床試験を立案することを目的とする。

Outline of Final Research Achievements

EGFR tyrosine kinase inhibitors (TKIs) transiently inhibit but can not eradicate lung cancer with EGFR mutations . In this study, we independently established an EGFR-mutant lung cancer syngeneic mouse model and evaluated how cancer cells escape from EGFR-TKI in coordinated with tumor microenvironment.
We found that EGFR signaling induces an immunosuppressive tumor microenvironment and that EGFR-TKI induces CD8-positive T cells dependent antitumor immunity. Sequential administration of PD-1 and VEGFR2 inhibitors following the treatment with EGFR-TKI further boosted the anti-tumor immunity.

Academic Significance and Societal Importance of the Research Achievements

EGFR肺癌は、非喫煙者肺癌の半数以上を占める重要な疾患である。日本人を含む東アジア人に特に発生頻度が高いこと、また若年発症例も多く認めることもあり、臨床的にも社会的にも重要性が高い。本研究は、EGFR-TKIががん細胞を直接阻害しているのみならず、腫瘍免疫を誘導することを初めて明らかにした。抗腫瘍免疫を最大化させることで、EGFR-TKIの治療効果の最大化、完全寛解を目指した治療戦略の発展が期待できる。

Research Products

• [Int'l Joint Research] University of Cologne(ドイツ)
• [Int'l Joint Research] University of Cologne(ドイツ)
• [Journal Article] MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I (2021)
  • Author(s): Bragelmann J, Lorenz C, Borchmann S, Nishii K, Wegner J, Meder L, Ostendorp J, Ast DF, Heimsoeth A, Nakasuka T, Hirabae A, Okawa S, et al, and Ohashi K, Schlee M, Sos ML.
  • Journal Title: Nat Commun. Volume: 12 Issue: 1 Pages: 5505-5505
  • DOI: 10.1038/s41467-021-25728-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Triple therapy with osimertinib, bevacizumab and cetuximab in EGFR-mutant lung cancer with HIF-1α/TGF-α expression (2021)
  • Author(s): Nishii K, Ohashi K, Watanabe H, Makimoto G, Nakasuka T, Higo H, Ninomiya K, Kato Y, Kubo T, Rai K, Ichihara E, Hotta K, Tabata M, Maeda Y, Kiura K.
  • Journal Title: Oncol Lett . Volume: 22(3) Issue: 3 Pages: 639-639
  • DOI: 10.3892/ol.2021.12900
  • NAID: 120007185583
  • Peer Reviewed / Open Access
• [Journal Article] A novel osimertinib-resistant human lung adenocarcinoma cell line harbouring mutant EGFR and activated IGF1R (2021)
  • Author(s): Makimoto G, Ninomiya K, Kubo T, Sunami R, Kato Y, Ichihara E, Ohashi K, Rai K, Hotta K, Tabata M, Maeda Y, Kiura K.
  • Journal Title: Jpn J Clin Oncol. Volume: 51 Issue: 6 Pages: 956-965
  • DOI: 10.1093/jjco/hyab048
  • Peer Reviewed
• [Journal Article] A case of dramatic reduction in cancer-associated thrombus following initiation of pembrolizumab in patient with a poor performance status and PD-L1+ lung adenocarcinoma harboring CCDC6-RET fusion gene and NF1/TP53 mutations. (2021)
  • Author(s): Nakasuka T, Ohashi K, Watanabe H, Kubo T, Matsumoto S, Goto K, Hotta K, Maeda Y, Kiura K.
  • Journal Title: Lung Cancer. Volume: 156 Pages: 1-4
  • DOI: 10.1016/j.lungcan.2021.03.022
  • Peer Reviewed / Open Access
• [Journal Article] Survival of chemo-naive patients with EGFR mutation-positive advanced non-small cell lung cancer after treatment with afatinib and bevacizumab: updates from the Okayama Lung Cancer Study Group Trial 1404 (2021)
  • Author(s): Ninomiya T, Nogami N, Kozuki T, Harada D, Kubo T, Ohashi K, Ichihara E, Kuyama S, Kudo K, Bessho A, Sakugawa M, Fujimoto N, Aoe K, Minami D, Sugimoto K, Ochi N, Takigawa N, Hotta K, Maeda Y, Kiura K.
  • Journal Title: Jpn J Clin Oncol . Volume: 51(8) Issue: 8 Pages: 1269-1276
  • DOI: 10.1093/jjco/hyab084
  • Peer Reviewed
• [Journal Article] Phase 1/2 study of alectinib in RET-rearranged previously-treated non-small cell lung cancer (ALL-RET) (2021)
  • Author(s): Takeuchi Shinji、Yanagitani Noriko、Seto Takashi、Hattori Yoshihiro、Ohashi Kadoaki、Morise Masahiro、Matsumoto Shingo、Yoh Kiyotaka、Goto Koichi、Nishio Makoto、Takahara Shizuko、Kawakami Takahiro、Imai Yasuhito、Yoshimura Kenichi、Tanimoto Azusa、Nishiyama Akihiro、Murayama Toshinori、Yano Seiji
  • Journal Title: Translational Lung Cancer Research Volume: 10 Issue: 1 Pages: 314-325
  • DOI: 10.21037/tlcr-20-549
  • Peer Reviewed / Open Access
• [Journal Article] Capmatinib in Japanese patients with MET exon 14 skipping-mutated or MET-amplified advanced NSCLC: GEOMETRY mono-1 study (2021)
  • Author(s): Seto T, Ohashi K, Sugawara S, Nishio M, Takeda M, Aoe K, Moizumi S, Nomura S, Tajima T, Hida T.
  • Journal Title: Cancer Sci. Volume: 112(4) Issue: 4 Pages: 1556-1566
  • DOI: 10.1111/cas.14826
  • Peer Reviewed / Open Access
• [Journal Article] Comparison of bronchoscopy and computed tomography-guided needle biopsy for re-biopsy in non-small cell lung cancer patients (2021)
  • Author(s): Kano H, Kubo T, Ninomiya K, Ichihara E, Ohashi K, Rai K, Hotta K, Tabata M, Hiraki T, Kanazawa S, Maeda Y, Kiura K.
  • Journal Title: Respir Investig . Volume: 59(2) Issue: 2 Pages: 240-246
  • DOI: 10.1016/j.resinv.2020.12.001
  • Peer Reviewed
• [Journal Article] Successful Re-administration of Osimertinib in Osimertinib-induced Interstitial Lung Disease with an Organizing Pneumonia Pattern: A Case Report and Literature Review (2020)
  • Author(s): Itano J, Higo H, Ohashi K, Makimoto G, Nishii K, Hotta K, Miyahara N, Maeda Y, Kiura K.
  • Journal Title: Internal Medicine Volume: 59 Issue: 6 Pages: 823-828
  • DOI: 10.2169/internalmedicine.3689-19
  • NAID: 130007808796
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2020-03-15
  • Peer Reviewed / Open Access
• [Journal Article] Detection of epidermal growth factor receptor mutations in exhaled breath condensate using droplet digital polymerase chain reaction. (2020)
  • Author(s): Nishii K, Ohashi K, Tamura T, Ninomiya K, Matsubara T, Senoo S, Kano H, Watanabe H, Oda N, Makimoto G, Higo H, Kato Y, Ninomiya T, Kubo T, Yamamoto H, Tomida S, Hotta K, Tabata M, Toyooka S, Maeda Y, Kiura K.
  • Journal Title: Oncol Lett Volume: 6 Issue: 6 Pages: 393-393
  • DOI: 10.3892/ol.2020.12256
  • NAID: 120007029912
  • Peer Reviewed
• [Journal Article] Impact of HER2 expression on EGFR-TKI treatment outcomes in lung tumors harboring EGFR mutations: A HER2-CS study subset analysis. (2020)
  • Author(s): Ohashi K, Ninomiya K, Yoshioka H, Bessho A, Shibayama T, Aoe K, Ishikawa N, Kozuki T, Kawai H, Kuyama S, Miyoshi S, Fujitaka K, Obata H, Tsubata Y, Awaya Y, Inoue M, Inoue K, Horita N, Yanai H, Hotta K, Kiura K.
  • Journal Title: Lung Cancer. Volume: 150 Pages: 83-89
  • DOI: 10.1016/j.lungcan.2020.09.024
  • Peer Reviewed
• [Journal Article] Share Beneficial effect of erlotinib and trastuzumab emtansine combination in lung tumors harboring EGFR mutations. (2020)
  • Author(s): Kayatani H, Ohashi K, Ninomiya K, Makimoto G, Nishii K, Higo H, Watanabe H, Kano H, Kato Y, Ninomiya T, Kubo T, Rai K, Ichihara E, Hotta K, Tabata M, Maeda Y, Kiura K.
  • Journal Title: Biochem Biophys Res Commun. Volume: 532(3) Issue: 3 Pages: 341-346
  • DOI: 10.1016/j.bbrc.2020.07.055
  • Peer Reviewed
• [Journal Article] A Long-term Response to Nivolumab in a Case of PD-L1-negative Lung Adenocarcinoma with an <i>EGFR</i> Mutation and Surrounding PD-L1-positive Tumor-associated Macrophages (2019)
  • Author(s): Watanabe H, Ohashi K, Nishii K, Seike K, Makimoto G, Hotta K, Maeda Y, Kiura K.
  • Journal Title: Internal Medicine Volume: 58 Issue: 20 Pages: 3033-3037
  • DOI: 10.2169/internalmedicine.2875-19
  • NAID: 130007728791
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2019-10-15
  • Peer Reviewed / Open Access
• [Journal Article] Beneficial Effect of Osimertinib Readministration in Non-small-cell Lung Cancer Harboring an Epidermal Growth Factor Receptor (<i>EGFR</i>) Mutation with a History of Acquired Resistance to Osimertinib (2019)
  • Author(s): Makimoto G, Ohashi K, Senoo S, Hotta K, Maeda Y, Kiura K
  • Journal Title: Internal Medicine Volume: 58 Issue: 11 Pages: 1625-1627
  • DOI: 10.2169/internalmedicine.2152-18
  • NAID: 130007658147
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2019-06-01
  • Peer Reviewed / Open Access
• [Journal Article] EGFR-TKI acquired resistance in lung cancers harboring EGFR mutations in immunocompetent C57BL/6J mice. (2019)
  • Author(s): Higo H, Ohashi K, Makimoto G, Nishii K, Kudo K, Kayatani H, Watanabe H, Kano H, Ninomiya K, Hotta K, Maeda Y, Kiura K.
  • Journal Title: Lung Cancer Volume: 136 Pages: 86-93
  • DOI: 10.1016/j.lungcan.2019.08.019
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Rapid Acquisition of Alectinib Resistance in ALK-Positive Lung Cancer With High Tumor Mutation Burden. (2019)
  • Author(s): Makimoto G, Ohashi K, Tomida S, Nishii K, Matsubara T, Kayatani H, Higo H, Ninomiya K, Sato A, Watanabe H, Kano H, Ninomiya T, Kubo T, Rai K, Ichihara E, Hotta K, Tabata M, Toyooka S, Takata M, Maeda Y, Kiura K.
  • Journal Title: J Thorac Oncol. Volume: 11 Issue: 11 Pages: 2009-2018
  • DOI: 10.1016/j.jtho.2019.07.017
  • NAID: 120006871852
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Therapeutic stimulation of nucleic acid receptor RIG-I enhances efficacy of kinase inhibitor treatment in oncogene-driven tumors (2021)
  • Author(s): Johannes Bragelmann; Carina Lorenz; Sven Borchmann; Kazuya Nishii; Julia Wegner; Jenny Ostendorp; David Ast; Alena Heimsoeth; Philipp Lohneis; Thomas Zillinger; Roland Ullrich; Kadoaki Ohashi; Martin Schlee; Martin Sos
  • Organizer: AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics
  • Int'l Joint Research
• [Presentation] Novel combined immunotherapy with EGFR-TKI follow by dual blockade of PD-1 and VGFR2 in lung cancer harboring Egfr mutation. (2021)
  • Author(s): Kazuya Nishii,, Kadoaki Ohashi, Shuta Tomida, Takamasa Nakasuka, Atsuko Hirabae, Sachi Okawa, Hisao Higo, Hiromi Watanabe, Hirohisa Kano, Chihiro Ando, Go Makimoto, Kiichiro Ninomiya,et al and Heiichiro Udono, Yoshinobu Maeda, Katsuyuki Kiura
  • Organizer: 1st JCA-AACR Precision Cancer Medicine International Conference
  • Int'l Joint Research
• [Presentation] Increased expression of amphiregulin may contribute to crizotinib resistance in lung cancer cells harboring ROS1 fusion genes (2021)
  • Author(s): Hiromi Watanabe, Yuka Kato, Kadoaki Ohashi, Shuta Tomida, Kenji Takada, Kazuya Nishii, Go Makimoto, Kiichiro Ninomiya, Masanori Fujii, Toshio Kubo, Eiki Ichihara, Yoshinobu Maeda, Katsuyuki Kiura
  • Organizer: 1st JCA-AACR Precision Cancer Medicine International Conference
  • Int'l Joint Research
• [Presentation] Combined efect of Lorlatinib and Bcl-2 inhibitors in intrinsic Alectinib resistant Lung Adenocarcinoma Harboring the EML4-ALK Fusion Gene (2021)
  • Author(s): Go Makimoto, Kadoaki Ohashi, Shuta Tomida, Kenji Takada, Hiromi Watanabe, Kazuya Nishii, Kiichiro Ninomiya, Yuka Kato, Toshio Kubo, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Yoshinobu Maeda and Katsuyuki Kiura
  • Organizer: 1st JCA-AACR Precision Cancer Medicine International Conference
  • Int'l Joint Research
• [Presentation] Egfr改変肺癌マウスモデルを用いたpersisterがん細胞に対する根治的薬物療法の開発 (2020)
  • Author(s): 大川祥，大橋圭明，原尚史，西井和也，中須賀崇匡，平生敦子，安東千裕，狩野裕久，渡邉洋美，二宮貴一朗，加藤有加，久保寿夫，頼冠名，市原英基，堀田勝幸，田端雅弘，前田嘉信，木浦勝行
  • Organizer: 第61回日本肺癌学会学術集会
• [Presentation] Egfr改変肺癌マウスモデルを用いたEGFR-TKI、抗VEGFR-2抗体と抗PD-1抗体併用療法の検討 (2020)
  • Author(s): 西井 和也, 大橋 圭明, 中須賀 崇匡, 平生 敦子, 大川 祥, 渡邉 洋美, 狩野 裕久, 原 尚史, 安東 千裕, 二宮 貴一朗, 加藤 有加, 二宮 崇, 久保 寿夫, 頼 冠名, 市原 英基, 堀田 勝幸, 田端 雅弘, (鵜殿平一郎 ), 前田 嘉信, 木浦勝行
  • Organizer: 第61回日本肺癌学会学術集会
• [Presentation] Tumor immunoediting in a lung cancer mouse model harboring EGFR mutations (2019)
  • Author(s): Kazuya Nishii, Kadoaki Ohashi, Kiichiro Ninomiya, Go Makimoto, Hiromi Watanabe, Hirohisa Kano, Naofumi Hara, Heiichiro Udono and Katsuyuki Kiura
  • Organizer: American Association for Cancer Research (AACR) 2019
  • Int'l Joint Research
• [Presentation] Rapid acquired resistance to alectinib in ALK-positive lung cancers with high tumor mutation burden (2019)
  • Author(s): Kadoaki Ohashi, Go Makimoto, Shuta Tomida, Kazuya Nishii, Shinichi Toyooka and Katsuyuki Kiura
  • Organizer: American Association for Cancer Research (AACR) 2019
  • Int'l Joint Research