Exploration of predictive molecular biomarkers for acquired resistance mechanisms to EGFR tyrosine kinase inhibitors

• Project/Area Number: 18K07336
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Kindai University
• Principal Investigator: Suda Kenichi 近畿大学, 医学部, 講師 (30631593)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: EGFR遺伝子変異 / 肺腺がん / 分子標的治療薬 / 獲得耐性 / tumor heterogeneity / 分子標的治療 / Drug tolerance / 上皮間葉転換 / CD44

Outline of Final Research Achievements

During the study period, we could not identify pre-treatment molecular biomarkers that predicts the acquired resistance mechanisms to EGFR-tyrosine kinase inhibitors (TKIs). However, we observed that the mechanisms by which cancer cells survive in the early stage of EGFR-TKI exposure differs depending on the type of TKI, and that RYK is one of the mechanisms. We also examined inter-tumor heterogeneity of acquired resistance mechanisms to EGFR-TKIs in the same patients. We observed that two different resistance mechanisms have developed, depending on the metastatic sites, in about half of the patients.
In addition, during the study period, several novel molecular-targeted agents have been developed for lung cancers with MET exon 14 skipping mutation, KRAS G12C mutation, EGFR and HER2 exon 20 insertion mutations (and some have been already approved for clinical use), therefore, we also explored acquired resistance mechanisms to these agents.

Academic Significance and Societal Importance of the Research Achievements

EGFR遺伝子変異のある肺がん（本邦では肺腺がんの約半数を占めるとされている）において、第一選択の薬物療法はEGFRキナーゼ阻害剤（EGFR-TKI）である。EGFR-TKIは著明な臨床効果を示すが、約1～2年以内に薬剤耐性が出現し、その耐性機序は多岐にわたることが報告されている。本研究では、①耐性機序を治療開始前のバイオマーカーで予測可能か、②（耐性獲得前の）EGFR-TKI治療早期にがん細胞が生き残るメカニズム、③同一患者内の異なる病巣で耐性機序が異なる場合があるか、ある場合はその頻度、についての検討を通して、獲得耐性を克服するために必要な基礎データを創出した。

Research Products

• [Journal Article] Utility of the Ba/F3 cell system for exploring on-target mechanisms of resistance to targeted therapies for lung cancer. (2022)
  • Author(s): Koga T, Suda K, Mitsudomi T.
  • Journal Title: Cancer Science Volume: 113 Issue: 3 Pages: 815-827
  • DOI: 10.1111/cas.15263
  • Peer Reviewed / Open Access
• [Journal Article] Frequent EGFR Mutations and Better Prognosis in Positron Emission Tomography-Negative, Solid-Type Lung Cancer. (2022)
  • Author(s): Suda K, Ohara S, Fujino T, Hamada A, M Chiba, Shimoji M, Takemoto T, Soh J, Mitsudomi T.
  • Journal Title: Clinical Lung Cancer Volume: 23 Issue: 1 Pages: e60-e68
  • DOI: 10.1016/j.cllc.2021.10.003
  • Peer Reviewed
• [Journal Article] 肺癌の分子標的治療の現状と展望. (2022)
  • Author(s): 須田健一, 光冨徹哉.
  • Journal Title: 胸部外科 Volume: 75 Pages: 53-66
  • NAID: 40022786239
• [Journal Article] Lung Cancer with MET exon 14 Skipping Mutation: Genetic Feature, Current Treatments, and Future Challenges. (2021)
  • Author(s): Fujino T, Suda K, Mitsudomi T.
  • Journal Title: Lung Cancer: Targets and Therapy Volume: 12 Pages: 35-50
  • DOI: 10.2147/lctt.s269307
  • Peer Reviewed / Open Access
• [Journal Article] 早期肺がんへのLiquid biopsyの応用 -再発予測としてのMinimal Residual Disease検出の意義-. (2021)
  • Author(s): 小原秀太, 須田健一, 光冨徹哉.
  • Journal Title: 近畿大学医学雑誌 Volume: 46 Pages: 73-78
• [Journal Article] Activity and mechanism of acquired resistance to tarloxotinib in HER2 mutant lung cancer: an in vitro study. (2021)
  • Author(s): Koga T, Suda K, Nishino M, Fujino T, Ohara S, Hamada A, Soh J, Tirunagaru V, Vellanki A, Doebele RC, Mitsudomi T.
  • Journal Title: Translational Lung Cancer Research Volume: 10 Issue: 8 Pages: 3659-3670
  • DOI: 10.21037/tlcr-21-216
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] KRAS Secondary Mutations That Confer Acquired Resistance to KRAS G12C Inhibitors, Sotorasib and Adagrasib, and Overcoming Strategies: Insights From In_Vitro Experiments. (2021)
  • Author(s): Koga T, Suda K, Fujino T, Ohara S, Hamada A, Nishino M, Chiba M, Shimoji M, Takemoto T, Arita R, Gmachl M, Hofmann MH, Soh J, Mitsudomi T.
  • Journal Title: Journal of Thoracic Oncology Volume: 16 Issue: 8 Pages: 1321-1332
  • DOI: 10.1016/j.jtho.2021.04.015
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] In vitro validation study of HER2 and HER4 mutations identified in an ad hoc secondary analysis of the LUX-Lung 8 randomized clinical trial. (2021)
  • Author(s): Hamada A, Suda K, Koga T, Fujino T, Nishino M, Ohara S, Chiba M, Shimoji M, Takemoto T, Soh J, Uchida T, Mitsudomi T.
  • Journal Title: Lung Cancer Volume: 162 Pages: 79-85
  • DOI: 10.1016/j.lungcan.2021.10.014
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Drug Tolerance to EGFR Tyrosine Kinase Inhibitors in Lung Cancers with EGFR Mutations. (2021)
  • Author(s): Suda K, Mitsudomi T.
  • Journal Title: Cells Volume: 10 Issue: 7 Pages: 1590-1590
  • DOI: 10.3390/cells10071590
  • Peer Reviewed / Open Access
• [Journal Article] Recent Advances in Cancer Immunotherapy. (2021)
  • Author(s): Suda K.
  • Journal Title: Biomolecules Volume: 11 Issue: 2 Pages: 335-335
  • DOI: 10.3390/biom11020335
  • Peer Reviewed / Open Access
• [Journal Article] Cell Line Models for Acquired Resistance to First-Line Osimertinib in Lung Cancers-Applications and Limitations (2021)
  • Author(s): Ohara S, Suda K, Mitsudomi T
  • Journal Title: Cells Volume: 10 Issue: 2 Pages: 354-354
  • DOI: 10.3390/cells10020354
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dose-dependence in acquisition of drug tolerant phenotype and high RYK expression as a mechanism of osimertinib tolerance in lung cancer (2021)
  • Author(s): Ohara S, Suda K, Fujino T, Hamada A, Koga T, Nishino M, Chiba M, Shimoji M, Takemoto T, Soh J, Mitsudomi T
  • Journal Title: Lung Cancer Volume: 154 Pages: 84-91
  • DOI: 10.1016/j.lungcan.2021.02.017
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Inter- and Intratumor Heterogeneity of EGFR Compound Mutations in Non-Small Cell Lung Cancers: Analysis of Five Cases (2021)
  • Author(s): Suda K, Sakai K, Obata K, Ohara S, Fujino T, Koga T, Hamada A, Soh J, Nishio K, Mitsudomi T
  • Journal Title: Clinical Lung Cancer Volume: 22 Issue: 2 Pages: e141-e145
  • DOI: 10.1016/j.cllc.2020.09.009
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Emerging oncogenic fusions other than ALK, ROS1, RET, and NTRK in NSCLC and the role of fusions as resistance mechanisms to targeted therapy (2020)
  • Author(s): Suda K, Mitsudomi T
  • Journal Title: Translational Lung Cancer Research Volume: 9 Issue: 6 Pages: 2618-2628
  • DOI: 10.21037/tlcr-20-186
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Spatial heterogeneity of acquired resistance mechanisms to 1st/2nd generation EGFR tyrosine kinase inhibitors in lung cancer (2020)
  • Author(s): Suda K, Murakami I, Obata K, Sakai K, Fujino T, Koga T, Ohara S, Hamada A, Soh J, Nishio K, Mitsudomi T
  • Journal Title: Lung Cancer Volume: 148 Pages: 100-104
  • DOI: 10.1016/j.lungcan.2020.08.010
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Emerging MET tyrosine kinase inhibitors for the treatment of non-small cell lung cancer (2020)
  • Author(s): Fujino T, Suda K, Mitsudomi T
  • Journal Title: Expert Opinion on Emerging Drugs Volume: 25 Issue: 3 Pages: 229-249
  • DOI: 10.1080/14728214.2020.1791821
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Prognostic value of plasma fibrinogen and D-dimer levels in patients with surgically resected non-small cell lung cancer (2020)
  • Author(s): Ohara S, Suda K, Tomizawa K, Takemoto T, Fujino T, Hamada A, Koga T, Nishino M, Chiba M, Sato K, Shimoji M, Soh J, Mitsudomi T
  • Journal Title: Surgery Today Volume: 50 Issue: 11 Pages: 1427-1433
  • DOI: 10.1007/s00595-020-02019-1
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Comparison of PD-L1 Expression Status Between Pure-Solid Versus Part-Solid Lung Adenocarcinomas. (2019)
  • Author(s): Suda K, Shimoji M, Shimizu S, Sato K, Chiba M, Tomizawa K, Takemoto T, Soh J, Mitsudomi T.
  • Journal Title: Biomolecules Volume: 9 Issue: 9 Pages: 456-456
  • DOI: 10.3390/biom9090456
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The ABCs of Preventing Hyperprogressive Disease After Immunotherapy: Awareness, Biomarkers, and Combination. (2019)
  • Author(s): Suda K.
  • Journal Title: Journal of Thoracic Disease Volume: 11 (Suppl 3) Issue: S3 Pages: S347-S351
  • DOI: 10.21037/jtd.2018.12.112
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sensitivity and Resistance of MET Exon 14 Mutations in Lung Cancer to Eight MET Tyrosine Kinase Inhibitors In Vitro (2019)
  • Author(s): Fujino T, Kobayashi Y, Suda K, Koga T, Nishino M, Ohara S, Chiba M, Shimoji M, Tomizawa K, Takemoto T, Mitsudomi T.
  • Journal Title: Journal of Thoracic Oncology Volume: 14 Issue: 10 Pages: 1753-1765
  • DOI: 10.1016/j.jtho.2019.06.023
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] For a better adjuvant strategy for resected lung cancer-lessons from treatment failure patterns of the ADJUVANT trial (CTONG 1104). (2019)
  • Author(s): Suda K.
  • Journal Title: Translational Lung Cancer Research Volume: 8 (Suppl 4) Issue: S4 Pages: S395-S399
  • DOI: 10.21037/tlcr.2019.08.24
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CD44 Facilitates Epithelial-to-Mesenchymal Transition Phenotypic Change at Acquisition of Resistance to EGFR Kinase Inhibitors in Lung Cancer. (2018)
  • Author(s): Suda K, Murakami I, Yu H, Kim J, Tan AC, Mizuuchi H, Rozeboom L, Ellison K, Rivard CJ, Mitsudomi T, Hirsch FR
  • Journal Title: Molecular Cancer Therapeutics Volume: 10 Pages: 2257-2265
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Innate Genetic Evolution of Lung Cancers and Spatial Heterogeneity: Analysis of Treatment-Naive Lesions. (2018)
  • Author(s): Suda K, Kim J, Murakami I, Rozeboom L, Shimoji M, Shimizu S, Rivard CJ, Mitsudomi T, Tan AC, Hirsch FR
  • Journal Title: Journal of Thoracic Oncology Volume: 10 Issue: 10 Pages: 1496-1507
  • DOI: 10.1016/j.jtho.2018.05.039
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effects of secondary EGFR mutations on resistance against upfront osimertinib in cells with EGFR-activating mutations in vitro. (2018)
  • Author(s): Nishino M, Suda K, Kobayashi Y, Ohara S, Fujino T, Koga T, Chiba M, Shimoji M, Tomizawa K, Takemoto T, Mitsudomi T
  • Journal Title: Lung Cancer Volume: 126 Pages: 149-155
  • DOI: 10.1016/j.lungcan.2018.10.026
  • Peer Reviewed
• [Journal Article] Intraoperative molecular imaging-a bright navigator for thoracic surgeons in the era of limited resection. (2018)
  • Author(s): Suda K
  • Journal Title: Translational Lung Cancer Research Volume: Suppl 3. Issue: S3 Pages: S232-S235
  • DOI: 10.21037/tlcr.2018.08.13
  • Peer Reviewed / Open Access
• [Presentation] 「pN 陽性」非小細胞肺がんにおけるすりガラス成分の有無の予後因子としての意義 (2021)
  • Author(s): 須田健一、小原秀太、西野将矢、古賀教将、藤野智大、濱田顕、千葉眞人、武本智樹、宗淳一、光冨徹哉
  • Organizer: 第38回日本呼吸器外科学会学術集会
• [Presentation] 病理病期 IA2-IIA 期 EGFR 変異肺がんに対するUFT術後補助療法の有用性 (2021)
  • Author(s): 須田健一、濱田顕、小原秀太、藤野智大、古賀教将、 西野将矢、千葉眞人、下治正樹、武本智樹、宗淳一、光冨徹哉
  • Organizer: 第62回日本肺癌学会学術集会
• [Presentation] EGFR 肺がん外科切除例の特徴と予後 －周術期分子標的治療を視野に入れて (2021)
  • Author(s): 須田健一、光冨徹哉
  • Organizer: 第62回日本肺癌学会学術集会
  • Invited
• [Presentation] Inter-tumor heterogeneity of CD44 expression in non-small cell lung cancers / EGFR-mutated lung adenocarcinomas (2021)
  • Author(s): Suda K, Rivard CJ, Yu H, Fujino T, Koga T, Soh J, Hirsch FR, Mitsudomi T.
  • Organizer: 2021 World Conference on Lung Cancer
  • Int'l Joint Research
• [Presentation] TKI耐性2次的変異を同定する手法としてのBa/F3細胞モデルの有用性 (2021)
  • Author(s): 須田健一，古賀教将，藤野智大，濵田顕，宗淳一，光冨徹哉
  • Organizer: 第115回日本肺癌学会関西支部学術集会
• [Presentation] Pure solid を呈するもPET 陰性であった原発性肺癌の臨床病理学的特徴 (2020)
  • Author(s): 須田健一、小原秀太、西野将矢、藤野智大、古賀 教将、濱田顕、千葉眞人、武本智樹、宗淳一、光冨徹哉
  • Organizer: 第120回日本外科学会定期学術集会
• [Presentation] 掻把術にて根治できなかった難治性術後膿胸に対するクリスタ ルバイオレットを用いた胸腔内洗浄の有用性 (2020)
  • Author(s): 須田健一、小原秀太、西野将矢、古賀教将、藤野智大、濱田顕、千葉眞人、武本智樹、 宗淳一、光冨徹哉
  • Organizer: 第37回日本呼吸器外科学会学術集会
• [Presentation] Inter- and intra-tumor heterogeneity of EGFR compound mutations in lung adenocarcinoma (2020)
  • Author(s): Suda K, Sakai K, Obata K, Ohara S, Fujino T, Koga T, Hamada A, Soh J, Nishio K, Mitsudomi T
  • Organizer: 第61回日本肺癌学会学術集会
• [Presentation] 第1/2世代 EGFR キナーゼ阻害剤に対する獲得耐性機序の inter-tumor heterogeneity とその臨床的意義 (2020)
  • Author(s): 須田健一、村上功、小畑慶子、藤野智大、坂井和子、宗淳一、西尾和人、光冨徹哉
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] EGFR変異肺がんにおけるEGFRチロシンキナーゼ阻害剤耐性克服を目指したトランスレーショナルリサーチ (2020)
  • Author(s): 須田健一、光冨徹哉
  • Organizer: 第79回日本癌学会学術総会
  • Invited
• [Presentation] Comparison of PD-L1 expression status between pure-solid versus part-solid tumors in lung adenocarcinomas. (2019)
  • Author(s): Suda K, Shimizu S, Shimoji M, Sato K, Ohara S, Fujino T, Nishino M, Koga T, Hamada A, Tomizawa K, Takemoto T, Soh J, Mitsudomi T.
  • Organizer: 2019 World Conference on Lung Cancer
  • Int'l Joint Research
• [Presentation] T790M or C797S confers acquired resistance to tarloxotinib and poziotinibin EGFR exon 20 insertion-driven lung cancer models in vitro. (2019)
  • Author(s): Suda K, Nishino M, Koga T, Fujino T, Ohara S, Soh J, Vellanki A, Tirunagaru V, Mitsudomi T.
  • Organizer: 2019 World Conference on Lung Cancer
  • Int'l Joint Research
• [Presentation] Potent in vitro activity of Tarloxotinib for EGFR C797S and other mutations refractory to current EGFR tyrosine kinase inhibitors (2019)
  • Author(s): Suda K, Nishino M, Koga T, Fujino T, Kobayashi Y, Mitsudomi T, Vellanki A, Tirunagaru V.
  • Organizer: AACR Annual Meeting 2019
  • Int'l Joint Research
• [Presentation] 肺腺がんにおけるPD-L1発現ーすりガラス陰影の有無との関連 (2019)
  • Author(s): 須田健一、下治正樹、西野将矢、藤野智大、古賀教将、小原秀太、千葉眞人、武本智樹、清水重喜、光冨徹哉
  • Organizer: 第119回日本外科学会定期学術集会
• [Presentation] CD44 Facilitates Epithelial-to-Mesenchymal Transition Phenotypic Change at Acquisition of Resistance to EGFR Kinase Inhibitors in Lung Cancer. (2019)
  • Author(s): 須田健一
  • Organizer: 第119回日本外科学会定期学術集会
  • Invited
• [Presentation] 自己免疫疾患を有する非小細胞肺癌切除例の短期成績と長期予後 (2019)
  • Author(s): 須田健一、小原秀太、西野将矢、千葉眞人、武本智樹、宗淳一、光冨徹哉
  • Organizer: 第72回日本胸部外科学会定期学術集会
• [Presentation] pStage IA NSCLCs with ground-glass opacity: are their candidates for Tegafur/Uracil adjuvant chemotherapy? (2019)
  • Author(s): Suda K, Ohara S, Koga T, Fujino T, Hamada A, Nishino M, Chiba M, Takemoto T, Soh J, Mitsudomi T.
  • Organizer: 第60回日本肺癌学会学術集会
• [Presentation] IASLC5: The importance of IASLC Membership for career development opportunities: My personal experience. (2019)
  • Author(s): Suda K.
  • Organizer: 第60回日本肺癌学会学術集会
  • Invited
• [Presentation] 腸型肺腺がんの3切除例 (2019)
  • Author(s): 須田健一、清水重喜、小原秀太、西野将矢、藤野智大、古賀教将、千葉眞人、下治正樹、武本智樹、光冨徹哉
  • Organizer: 第109回日本肺癌学会関西支部会
• [Presentation] EGFR-TKI 獲得耐性に伴う上皮間葉転換（EMT）におけるCD44 の役割 (2018)
  • Author(s): 須田健一、村上功、JihyeKim、Christopher J. Rivard、光冨徹哉、Fred R. Hirsch
  • Organizer: 第118回日本外科学会定期学術集会
• [Presentation] EGFR キナーゼ阻害剤獲得耐性における分子異常の heterogeneity の検討とその克服 (2018)
  • Author(s): 須田健一
  • Organizer: 第118回日本外科学会定期学術集会
  • Invited
• [Presentation] Compound mutations: focusing on EGFR-mutated lung cancers (2018)
  • Author(s): Kenichi Suda
  • Organizer: 77th Annual Meeting of the Japanese Cancer Association
  • Invited
• [Presentation] Prediction and prevention of acquired resistance to EGFR-TKIs: a story of HCC4006 cells (2018)
  • Author(s): Kenichi Suda and Tetsuya Mitsudomi
  • Organizer: 第59回日本肺癌学会総会
  • Invited
• [Presentation] 早期非小細胞肺がんにおけるPD-L1発現－腫瘍発生部位に着目した検討 (2018)
  • Author(s): 須田健一、下治正樹、西野将矢、藤野智大、古賀教将、小原秀太、千葉眞人、武本智樹、清水重喜、光冨徹哉
  • Organizer: 第59回日本肺癌学会総会