Development of therapy for overcoming resistance to mutant selective EGFR-TKI due to persistance of apoptosis

• Project/Area Number: 17K09649
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Kanazawa University
• Principal Investigator: TAKEUCHI SHINJI 金沢大学, 附属病院, 講師 (90565384)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: EGFR変異 / 非小細胞肺癌 / アポトーシス / Osimertinib / HDAC阻害薬 / EGFR変異肺がん / BIM遺伝子多型 / HDAC3 / 癌 / トランスレーショナルリサーチ

Outline of Final Research Achievements

The BIM deletion polymorphism is associated with apoptosis resistance to EGFR-TKIs, such as gefitinib, in NSCLC harboring EGFR mutations. Here, we investigated whether the BIM deletion polymorphism contributes to resistance against osimertinib, a mutant selective EGFR-TKI.
EGFR-mutated NSCLC cell lines with the BIM deletion polymorphism exhibited apoptosis resistance to osimertinib and this resistance was overcome by combined use with vorinostat in vitro and in vivo. Experiments with homozygous BIM deletion-positive EGFR-mutated NSCLC cells revealed that vorinostat increased the expression of active BIM protein and induced apoptosis in osimertinib-treated cells. These effects were mediated predominantly by HDAC3 inhibition. These findings indicate the importance of developing HDAC3-selective inhibitors, and their combined use with osimertinib, for treating EGFR-mutated lung cancers carrying the BIM deletion polymorphism.

Academic Significance and Societal Importance of the Research Achievements

BIM遺伝子多型は少量の血液で解析が可能で、患者への侵襲が少なく、簡便かつ正確に解析することができるため、薬剤耐性のバイオマーカーとして非常に有望である。本研究により、EGFR変異肺癌の標準治療であるOsimertinibの耐性にもBIM遺伝子多型が影響しており、HDAC阻害薬であるVorinostat併用治療が有効であることが示唆された。今後、BIM遺伝子多型をバイオマーカーとしたHDAC阻害薬併用治療の臨床開発が進むことが期待される。

Research Products

• [Journal Article] Phase I study of vorinostat with gefitinib in BIM deletion polymorphism/epidermal growth factor receptor mutation double-positive lung cancer. (2020)
  • Author(s): Shinji Takeuchi, Tetsunari Hase, et al.
  • Journal Title: Cancer science Volume: 111 Issue: 2 Pages: 561-570
  • DOI: 10.1111/cas.14260
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Resminostat, a histone deacetylase inhibitor, circumvents tolerance to EGFR inhibitors in EGFR-mutated lung cancer cells with <i>BIM</i> deletion polymorphism (2020)
  • Author(s): Arai S, Yano S, et al.
  • Journal Title: The Journal of Medical Investigation Volume: 67 Issue: 3.4 Pages: 343-350
  • DOI: 10.2152/jmi.67.343
  • NAID: 130007936892
  • ISSN: 1343-1420, 1349-6867
  • Peer Reviewed
• [Journal Article] Osimertinib Overcomes Alectinib Resistance Caused by Amphiregulin in a Leptomeningeal Carcinomatosis Model of ALK-Rearranged Lung Cancer. (2020)
  • Author(s): Sachiko Arai, Shinji Takeuchi, Koji Fukuda, Hirokazu Taniguchi, Akihiro Nishiyama, Azusa Tanimoto, Miyako Satouchi, Kaname Yamashita, Koshiro Ohtsubo, Shigeki Nanjo, Toru Kumagai, Ryohei Katayama, Makoto Nishio, Mei-Mei Zheng, Yi-Long Wu, Hiroshi Nishihara, Takushi Yamamoto, Mitsutoshi Nakada, Seiji Yano
  • Journal Title: Journal of thoracic oncology Volume: 15 Issue: 5 Pages: 752-765
  • DOI: 10.1016/j.jtho.2020.01.001
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] Notch3-dependent β-catenin signaling mediates EGFR TKI drug persistence in EGFR mutant NSCLC. (2018)
  • Author(s): Arasada RR, Shilo K, Yamada T, Zhang J, Yano S, Ghanem R, Wang W, Takeuchi S, Fukuda K, Katakami N, Tomii K, Ogushi F, Nishioka Y, Talabere T, Misra S, Duan W, Fadda P, Rahman MA, Nana-Sinkam P, Evans J, Amann J, Tchekneva EE, Dikov MM, Carbone DP.
  • Journal Title: Nat Commun. Volume: 9 Issue: 1 Pages: 3198-3198
  • DOI: 10.1038/s41467-018-05626-2
  • NAID: 120006949473
  • 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] 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] 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: Clin Cancer Res. Volume: 23 Issue: 12 Pages: 3139-3149
  • DOI: 10.1158/1078-0432.ccr-16-2271
  • Peer Reviewed / Int'l Joint Research
• [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] Phase I study of combined therapy with vorinostat and gefitinib to treat <i>BIM</i> deletion polymorphism-associated resistance in <i>EGFR</i>-mutant lung cancer (VICTROY-J): a study protocol (2017)
  • Author(s): Takeuchi S, Yoshimura K, Fujiwara T, Ando M, Shimizu S, Nagase K, Hasegawa Y, Takahashi T, Katakami N, Inoue A, Yano S.
  • Journal Title: The Journal of Medical Investigation Volume: 64 Issue: 3.4 Pages: 321-325
  • DOI: 10.2152/jmi.64.321
  • NAID: 130006105349
  • ISSN: 1343-1420, 1349-6867
• [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
• [Presentation] 肺癌のアポトーシス抵抗性に起因する 分子標的薬耐性を克服する橋渡し研究 (2018)
  • Author(s): 竹内 伸司
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] 医師主導治験による肺がんの新規分子標的治療の開発 (2017)
  • Author(s): 竹内伸司
  • Organizer: 第15回日本臨床腫瘍学会学術集会
• [Presentation] New therapeutic strategies for overcoming resistance to targeted drugs in lung cancer by HDAC inhibition (2017)
  • Author(s): 竹内伸司
  • Organizer: 第76回日本癌学会学術総会
  • Invited