Study to circumvent targeted drug resistance in leptomeningeal carcinomatosis of lung cancer

• Project/Area Number: 16H05308
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Kanazawa University
• Principal Investigator: Yano Seiji 金沢大学, がん進展制御研究所, 教授 (30294672)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2018: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
• Keywords: 分子標的薬耐性 / 髄膜がん腫症 / EGFR-TKI / 髄膜がん種症 / 耐性変異 / 中枢神経系転移 / ALK阻害薬耐性 / NTRK1融合遺伝子陽性がん

Outline of Final Research Achievements

In the leptomeningeal carcinomatosis (LMC) model of EGFR mutated lung cancer, we demonstrated that MET copy number gain caused resistance to 1st generation EGFR-tyrosine kinase inhibitors (TKI) and that combined use of MET inhibitor overcame the resistance. We also discovered 2 mutations which caused resistance to 3rd generation EGFR-TKI, osimertinib, in the LMC model. In the LMC model of ALK-rearranged lung cancer, we found that amphiregulin, an EGFR ligand, induced resistance to ALK-TKI alectinib and that combined use of EGFR-TKI overcame the resistance. In the brain metastasis model of NTRK1-rearranged cancer, we showed that NTRK1-G667C mutation caused resistance to TRK-A inhibitor entrectinib and that foretinib circumvent the resistance.

Academic Significance and Societal Importance of the Research Achievements

本研究において、肺がんの髄膜がん腫症における分子標的薬耐性の新たなメカニズムが同定されるとともに治療法の候補が見つかったことから、近い将来耐性克服を目指す臨床試験が行われ成果が患者に還元される可能性が生まれた。

Research Products

• [Journal Article] Distribution and Activity of Lenvatinib in Brain Tumor Models of Human Anaplastic Thyroid Cancer Cells in Severe Combined Immune Deficient Mice (2019)
  • Author(s): Wang Rong、Yamada Tadaaki、Arai Sachiko、Fukuda Koji、Taniguchi Hirokazu、Tanimoto Azusa、Nishiyama Akihiro、Takeuchi Shinji、Yamashita Kaname、Ohtsubo Koshiro、Matsui Junji、Onoda Naoyoshi、Hirata Eishu、Taira Shu、Yano Seiji
  • Journal Title: Molecular Cancer Therapeutics Volume: x Issue: 5 Pages: 947-56
  • DOI: 10.1158/1535-7163.mct-18-0695
  • Peer Reviewed / Open Access
• [Journal Article] Epithelial-to-Mesenchymal Transition Is a Mechanism of ALK Inhibitor Resistance in Lung Cancer Independent of ALK Mutation Status. (2019)
  • Author(s): Fukuda K, Takeuchi S,Yano S, et al.
  • Journal Title: Cancer Res Volume: 79(7) Issue: 7 Pages: 1658-1670
  • DOI: 10.1158/0008-5472.can-18-2052
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Taniguchi H, Yamada T, Wang R, Tanimura K, Adachi Y, Nishiyama A, Tanimoto A, Takeuchi S, Araujo LH, Boroni M, Yoshimura A, Shiotsu S, Matsumoto I, Watanabe S, Kikuchi T, Miura S, Tanaka H, Kitazaki T, Yamaguchi H, Mukae H, Uchino J, Uehara H, Takayama K, Yano S. (2018)
  • Author(s): Taniguchi H, Yamada T, Wang R, Tanimura K, Adachi Y, Nishiyama A, Tanimoto A, Takeuchi S, Araujo LH, Boroni M, Yoshimura A, Shiotsu S, Matsumoto I, Watanabe S, Kikuchi T, Miura S, Tanaka H, Kitazaki T, Yamaguchi H, Mukae H, Uchino J, Uehara H, Takayama K, Yano S.
  • Journal Title: Nat Commun. Volume: 10 Issue: 1 Pages: 259-259
  • DOI: 10.1038/s41467-018-08074-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pulmonary carcinosarcoma showing an obvious response to pazopanib: a case report. (2018)
  • Author(s): Tanimoro A, Yano S, et al.
  • Journal Title: BMC Pulm Med Volume: 18(1) Issue: 1 Pages: 193-193
  • DOI: 10.1186/s12890-018-0757-7
  • Peer Reviewed
• [Journal Article] Foretinib Overcomes Entrectinib Resistance Associated with NTRK1 G667C Mutation in NTRK1 Fusion-Positive Tumor Cells in a Brain Metastasis Model (2018)
  • Author(s): Akihiro Nishiyama
  • Journal Title: Clinical Cancer Research Volume: 24 Issue: 10 Pages: 23572369-23572369
  • DOI: 10.1158/1078-0432.ccr-17-1623
  • Peer Reviewed
• [Journal Article] Distinct dependencies on receptor tyrosine kinases in the regulation of MAPK signaling between BRAF V600E and non-V600E mutant lung cancers (2018)
  • Author(s): Kotani Hiroshi、Adachi Yuta、Kitai Hidenori、Tomida Shuta、Bando Hideaki、Faber Anthony C.、Yoshino Takayuki、Voon Dominic C.、Yano Seiji、Ebi Hiromichi
  • Journal Title: Oncogene Volume: 37 Issue: 13 Pages: 1775-1787
  • DOI: 10.1038/s41388-017-0035-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Histone deacetylase inhibition enhances the antitumor activity of a MEK inhibitor in lung cancer cells harboring RAS mutations. Mol Cancer Ther 2018 17:17-25. doi: 10.1158/1535-7163.MCT-17-0146. (2018)
  • Author(s): Yamada T, Amann JM, Tanimoto A, Taniguchi H, Shukuya T, Timmers C, Yano S, Shilo K, Carbone DP.
  • Journal Title: Molecular Cancer Therapeutics Volume: 17 Pages: 17-25
  • Int'l Joint Research
• [Journal Article] Foretinib overcomes entrectinib resistance associated with the NTRK1 G667C mutation in NTRK1 fusion-positive tumor cells in a brain metastasis model. (2018)
  • Author(s): 22.Nishiyama A, Yamada T, Kita K, Wang R, Arai S, Fukuda K, Tanimoto A, Takeuchi S, Tange S, Tajima A, Furuya N, Kinoshita T, Yano S.
  • Journal Title: Clinical Cancer Research Volume: [Epub ahead of print]
  • Peer Reviewed
• [Journal Article] MET copy number gain is associated with gefitinib resistance in leptomeningeal carcinomatosis of EGFR-mutant lung cancer. (2017)
  • Author(s): Nanjo S, Arai S, Wang W, Takeuchi S, Yamada T, Hata A, Katakami N, Okada Y, Yano S.
  • Journal Title: Molecular Cancer Therapeutics Volume: 16 Pages: 506-15
  • Peer Reviewed
• [Journal Article] Histone deacetylase 3 inhibition overcomes BIM deletion polymorphism-mediated osimertinib-resistance in EGFR-mutant lung cancer. (2017)
  • Author(s): Tanimoto A, Takeuchi S, Arai S, Fukuda K, Yamada T, Roca X, Ong ST, Yano S.
  • Journal Title: Clinical Cancer Research Volume: 23 Pages: 3139-49
  • Peer Reviewed
• [Journal Article] n vitro and in vivo anti-tumor activity of alectinib in tumor cells with NCOA4-RET. (2017)
  • Author(s): Arai S*, Kita K*, Tanimoto A, Takeuchi T, Fukuda K, Sato H, Yano S. *: equally contribution.
  • Journal Title: Oncotarget Volume: 8 Issue: 43 Pages: 73766-73
  • DOI: 10.18632/oncotarget.17900
  • Peer Reviewed
• [Journal Article] Podoplanin promotes progression of malignant pleural mesothelioma by regulating motility and focus formation. (2017)
  • Author(s): Takeuchi S, Fukuda K, Yamada T, Arai S, Takagi S, Ishii G, Ochiai A, Iwakiri S, Itoi K, Uehara H, Nishihara H, Fujita N, Yano S.
  • Journal Title: Cancer Sci. Volume: 108 Issue: 4 Pages: 696-703
  • DOI: 10.1111/cas.13190
  • NAID: 120006306235
  • Peer Reviewed / Open Access
• [Journal Article] Impact of MET inhibition on small-cell lung cancer cells showing aberrant activation of the hepatocyte growth factor/MET pathway. (2017)
  • Author(s): Taniguchi H, Yamada T, Takeuchi S, Arai S, Fukuda K, Sakamoto S, Kawada M, Yamaguchi H, Mukae H, Yano S.
  • Journal Title: Cancer Sci. Volume: 108 Issue: 7 Pages: 1378-1385
  • DOI: 10.1111/cas.13268
  • Peer Reviewed / Open Access
• [Journal Article] Resistance mediated by alternative receptor tyrosine kinases in FGFR1-amplified lung cancer (2017)
  • Author(s): Adachi Yuta、Watanabe Kazuyoshi、Kita Kenji、Kitai Hidenori、Kotani Hiroshi、Sato Yuki、Inase Naohiko、Yano Seiji、Ebi Hiromichi
  • Journal Title: Carcinogenesis Volume: 38 Issue: 11 Pages: 1063-1072
  • DOI: 10.1093/carcin/bgx091
  • Peer Reviewed
• [Journal Article] In vivo imaging xenograft models for the evaluation of anti-brain tumor efficacy of targeted drugs. (2017)
  • Author(s): Kita K, Arai S, Nishiyama A, Taniguchi H, Fukuda K, Wang R, Yamada T, Takeuchi S, Tange S, Tajima A, Nakada M, Yasumoto K, Motoo Y, Murakami T, Yano S.
  • Journal Title: Cancer Med Volume: 6 Issue: 12 Pages: 2972-2983
  • DOI: 10.1002/cam4.1255
  • Peer Reviewed / Open Access
• [Journal Article] MET copy number gain is associated with gefitinib resistance in leptomeningeal carcinomatosis of EGFR- mutant lung cancer. (2017)
  • Author(s): Nanjo S, Arai S, Wang W, Takeuchi S, Yamada T, Hata A, Katakami N, Okada Y, Yano S.
  • Journal Title: Mol Cancer Ther Volume: 16 Issue: 3 Pages: 506-515
  • DOI: 10.1158/1535-7163.mct-16-0522
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Amphiregulin triggered EGFR activation confers crizotinib-resistance in a mouse model with EML4-ALK cancer and its circumvention with EGFR inhibitors. (2017)
  • Author(s): Taniguchi H, Takeuchi S, Fukuda K, Nakagawa T, Arai S, Yamada T, Yamaguchi H, Mukae H, Yano S.
  • Journal Title: Cancer Sci Volume: 108 Issue: 1 Pages: 53-60
  • DOI: 10.1111/cas.13111
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] High efficacy of third generation EGFR inhibitor AZD9291 in a leptomeningeal carcinomatosis model with EGFR-mutant lung cancer cells (2016)
  • Author(s): Nanjo S, Ebi H, Arai S, Takeuchi S, Yamada T, Mochizuki S, Okada Y, Nakada M, Murakami T, Yano S.
  • Journal Title: Oncotarget Volume: 7(4) Issue: 4 Pages: 3847-3856
  • DOI: 10.18632/oncotarget.6758
  • NAID: 120005830568
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Inter-Organ Heterogeneity on Mechanisms of Targeted Drug Resistance-Central Nervous System (CNS) vs Extra CNS-. (2018)
  • Author(s): Yano S.
  • Organizer: The 6th JCA-AACR Special Joint Conference
  • Int'l Joint Research / Invited
• [Presentation] Inter-Organ Heterogeneity on Mechanisms of Targeted Drug Resistance-Central Nervous System (CNS) vs Extra CNS-. (2018)
  • Author(s): Yano S.
  • Organizer: IASLC 19th World Conference on Lung Cancer. (WCLC)
  • Int'l Joint Research
• [Presentation] Foretinib circumvents the NTRK1 G667C mutation-associated entrectinib-resistance in the brain and liver metastases produced by NTRK1 fusion-positive tumor cells. (2018)
  • Author(s): Yano S.
  • Organizer: 10.European Society for Medical Oncology (ESMO) 2018 Congress
  • Int'l Joint Research
• [Presentation] 肺がんの新規分子標的治療を開発するトランスレーショナルリサーチ. (2017)
  • Author(s): 矢野聖二.
  • Organizer: 第57回日本呼吸器学会
  • Invited
• [Presentation] 分子標的薬の獲得耐性と耐性克服治療. (2017)
  • Author(s): 矢野聖二.
  • Organizer: 第15回日本臨床腫瘍学会学術集会
• [Presentation] NTRK1遺伝子異常を有する大腸癌細胞株におけるTRK阻害薬Entrectinib耐性機構の解明とその克服. (2017)
  • Author(s): 西山明宏,矢野聖二,他.
  • Organizer: 第26回日本がん転移学会学術集会総会
• [Presentation] SSP基礎講座・もっと知りたい分子標的薬. (2017)
  • Author(s): 矢野聖二.
  • Organizer: 第76回日本癌学会学術総会
  • Invited
• [Presentation] Challenge to overcome targeted drug resistance. (2017)
  • Author(s): Yano S.
  • Organizer: 5.Kanazawa University Cancer Research Institute the 50th Anniversary International Symposium 2017.
• [Presentation] Met copy number gain associates with gefitinib resistance in leptomeningeal carcinomatosis of EGFR mutant lung cancer. (2016)
  • Author(s): Yano S.
  • Organizer: The 17th World Conference on Lung Cancer (WCLC 2016)
  • Place of Presentation: Wienna
  • Int'l Joint Research
• [Presentation] 肺がんの髄膜がん腫症とEGFR-TKI耐性. (2016)
  • Author(s): 矢野聖二, 新井祥子, 福田康二, 山田忠明, 竹内伸司, 南條成輝, 片上信之, 岡田保典.
  • Organizer: 第25回日本がん転移学会学術集会総会
  • Place of Presentation: 米子市
  • Invited
• [Remarks] 金沢大学附属病院がんセンター
  • URL: http://syuyounaika.w3.kanazawa-u.ac.jp/
• [Remarks] 金沢大学附属病院がんセンター・金沢大学がん進展制御研究所
  • URL: http://syuyounaika.w3.kanazawa-u.ac.jp/