Development of therapy for circumvention of EGFR-TKI resistance due to BIM polymorphism in EGFR mutant lung cancer.

• Project/Area Number: 25860640
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Respiratory organ internal medicine
• Research Institution: Kanazawa University
• Principal Investigator: TAKEUCHI Shinji 金沢大学, がん進展制御研究所, 助教 (90565384)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2013: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: 肺癌 / EGFR変異 / アポトーシス / BIM遺伝子多型 / EGFR変異肺がん / BIM / HDAC阻害薬 / EGFR-TKI / apoptosis

Outline of Final Research Achievements

We investigated whether vorinostat, a histone deacetylase (HDAC) inhibitor, could circumvent EGFR-TKI resistance in the EGFR mutant lung cancer cell lines, which harbor the BIM polymorphism. We found that PC-3 cells with BIM polymorphism were much less sensitive to gefitinib-induced apoptosis than the EGFR mutant cell lines, which do not harbor this polymorphism. Vorinostat dose-dependently increased the expression of BIM with a pro-apoptotic BH3 domain and, together with gefitinib, induced apoptosis in cells with BIM polymorphism in vitro. In xenograft models, gefitinib did not induce regression of PC-3 subcutaneous tumors, whereas the combination of vorinostat and gefitinib induced marked regression of tumors, accompanied by tumor-cell apoptosis. These results indicate that the combination of HDAC inhibitor and EGFR-TKI may circumvent the resistance due to the BIM polymorphism in EGFR mutant lung cancer.

Research Products

• [Journal Article] In vivo imaging models of bone and brain metastases and pleural carcinomatosis with a novel human EML4-ALK lung cancer cell line. (2015)
  • Author(s): Nanjo S, Yano S, et al.
  • Journal Title: Cancer Sci Volume: 106 Issue: 3 Pages: 244-52
  • DOI: 10.1111/cas.12600
  • NAID: 120005830611
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Lack of association between the BIM deletion polymorphism and the risk of lung cancer with and without EGFR mutations. (2015)
  • Author(s): Ebi H, Yano S, et al.
  • Journal Title: J Thorac Oncol Volume: 10 Issue: 1 Pages: 59-66
  • DOI: 10.1097/jto.0000000000000371
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Clinical significance of epidermal growth factor receptor tyrosine kinase inhibitors: Sensitivity and resistance. (2014)
  • Author(s): Takeuchi S, Yano S.
  • Journal Title: Respir Investig Volume: 52 Issue: 6 Pages: 348-56
  • DOI: 10.1016/j.resinv.2014.10.002
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Receptor ligand-triggered resistance to alectinib and its circumvention by Hsp90 inhibition in EML4-ALK lung cancer cells. (2014)
  • Author(s): Tanimoto A, Yamada T, Nanjo S, Takeuchi S, Ebi H, Kita K, Matsumoto K, Yano S.
  • Journal Title: Oncotarget Volume: 5 Pages: 4920-4928
  • NAID: 120005830567
  • Peer Reviewed / Open Access
• [Journal Article] EGFR-TKI resistance due to BIM polymorphism can be circumvented in combination with HDAC inhibition. (2013)
  • Author(s): Nakagawa T, Yano S, et al.
  • Journal Title: Cancer Res Volume: 73 Issue: 8 Pages: 2428-34
  • DOI: 10.1158/0008-5472.can-12-3479
  • Peer Reviewed
• [Journal Article] mTOR inhibitors control erlotinib-resistance of EGFR mutant lung cancer cells triggered by HGF. (2013)
  • Author(s): Ishikawa D, Yano S, et al.
  • Journal Title: PLoS ONE Volume: 8 Issue: 5 Pages: e62104-e62104
  • DOI: 10.1371/journal.pone.0062104
  • Peer Reviewed
• [Journal Article] Paracrine activation of MET promotes peritoneal carcinomatosis in scirrhous gastric cancer. (2013)
  • Author(s): Zhao L, Yano S, et al.
  • Journal Title: Cancer Sci Volume: 104 Issue: 12 Pages: 1640-6
  • DOI: 10.1111/cas.12301
  • NAID: 120005830610
  • Peer Reviewed
• [Journal Article] Ability of the Met kinase inhibitor crizotinib and new generation EGFR inhibitors to overcome resistance to EGFR inhibitors. (2013)
  • Author(s): Nanjo S, Yamada T, Nishihara H, Takeuchi S, Sano T, Nakagawa T, Ishikawa D, Zhao L, Ebi H, Yasumoto K, Matsumoto K, Yano S.
  • Journal Title: PLoS One Volume: 8
  • NAID: 120005368227
  • Peer Reviewed
• [Presentation] BIM遺伝子多型によるEGFR-TKI耐性の治療法開発の現状 (2014)
  • Author(s): 竹内伸司、矢野聖二
  • Organizer: 第55回日本肺癌学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2014-11-14 – 2014-11-16
• [Presentation] Therapeutic strategies for overcoming resistance to EGFR-TKI and ALK-TKI by inhibition of Hsp90 or HADC (2014)
  • Author(s): 竹内伸司、矢野聖二
  • Organizer: 第12回日本臨床腫瘍学会学術集会
  • Place of Presentation: 福岡
  • Year and Date: 2014-07-17 – 2014-07-19
• [Presentation] EGFR-TKI耐性とその克服 (2014)
  • Author(s): 竹内伸司、矢野聖二
  • Organizer: 第18回日本がん分子標的治療学会学術集会
  • Place of Presentation: 仙台
  • Year and Date: 2014-06-25 – 2014-06-27
• [Presentation] EGFR変異肺がんのEGFR-TKI耐性 (2014)
  • Author(s): 竹内伸司、矢野聖二
  • Organizer: 第54回日本呼吸器学会学術講演
  • Place of Presentation: 大阪
  • Year and Date: 2014-04-25 – 2014-04-27
• [Presentation] BIM遺伝子多型に起因する分子標的薬耐性の克服
  • Author(s): 竹内伸司, 中川学之, 矢野聖二
  • Organizer: 第11回日本臨床腫瘍学会学術集会
  • Place of Presentation: 仙台
  • Invited
• [Presentation] EGFR-TKI resistance due to BIM polymorphism can be circumvented in combination with HDAC inhibition
  • Author(s): Takeuchi S, Nakagawa T, Yamada T, Yano S.
  • Organizer: IASLC 15th World Conference on Lung Cancer
  • Place of Presentation: シドニー
  • Invited
• [Presentation] BIM遺伝子多型に起因するEGFR-TKI耐性とHDAC阻害薬併用による耐性克服治療戦略
  • Author(s): 竹内伸司, 中川学之, 長谷川好規, 矢野聖二
  • Organizer: 第54回日本肺癌学会総会
  • Place of Presentation: 東京
  • Invited
• [Book] 分子呼吸器病 (2014)
  • Author(s): 竹内伸司、矢野聖二
  • Publisher: 先端医学社