HER2 target therapy for multidrug-resistant small cell lung cancer

• Project/Area Number: 24591165
• 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: Osaka University
• Principal Investigator: KIJIMA TAKASHI 大阪大学, 医学(系)研究科(研究院), 講師 (90372614)
• Co-Investigator(Kenkyū-buntansha): NAGATOMO Izumi 大阪大学, 大学院医学系研究科, 助教 (10570583) ; KOHMO Satoshi 大阪大学, 大学院医学系研究科, 招聘教員 (40625670) ; MINAMI Toshiyuki 大阪大学, 大学院医学系研究科, 助教 (00705113)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 小細胞肺癌 / 多剤耐性 / 分子標的治療 / HER2 / ラパチニブ / トラスツズマブ / ADCC / ICAM-1 / ベバシズマブ / ＨＥＲ２

Outline of Final Research Achievements

Small cell lung cancer (SCLC) is highly malignant because it easily acquires multidrug resistance. We have found that HER2 is upregulated on the cell surface of SCLC cells when they become multidrug-resistant. A HER2 tyrosine kinase inhibitor lapatinib recovered the sensitivity of chemoresistant SCLC cells by inhibiting the function of drug-efflux pumps ABCB1 and ABCG2 which were expressed on them. On the other hand, an anti-HER2 antibody trastuzumab exerted significant antitumor activity toward HER2-upregulated chemoresistant SCLC cells mainly via antibody-dependent cell-mediated cytotoxicity (ADCC) mechanism. Moreover, we treated two patients with HER2-positive relapsed SCLC by trastuzumab plus irinotecan combination therapy and confirmed the antitumor efficacy and safety in this clinical setting. These findings indicate the possibility of HER2 as therapeutic target to overcome multidrug-resistance of SCLC.

Research Products

• [Journal Article] Favorable response to trastuzumab plus irinotecan combination therapy in two patients with HER2-positive relapsed small-cell lung cancer. (2015)
  • Author(s): Kinehara Y, Minami T, Kijima T, Hoshino S, Morimura O, Otsuka T, Hayama Y, Fukushima K, Takeuchi Y, Higashiguchi M, Miyake K, Hirata H, Nagatomo I, Inoue K, Takeda Y, Kida H, Kumanogoh A.
  • Journal Title: Lung Cancer. Volume: 87 Issue: 3 Pages: 321-325
  • DOI: 10.1016/j.lungcan.2015.01.003
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Overcoming chemoresistance of small-cell lung cancer through stepwise HER2-targeted antibody-dependent cell-mediated cytotoxicity and VEGF-targeted antiangiogenesis. (2013)
  • Author(s): Minami T, Kijima T, Kohmo S, Arase H, Otani Y, Nagatomo I, Takahashi R, Miyake K, Higashiguchi M, Morimura O, Ihara S, Tsujino K, Hirata H, Inoue K, Takeda Y, Kida H, Tachibana I, Kumanogoh A.
  • Journal Title: Scientific Reports Volume: 3 Issue: 1 Pages: 2669-2669
  • DOI: 10.1038/srep02669
  • Peer Reviewed
• [Journal Article] HER2 as therapeutic target for overcoming ATP-binding cassette transporter-mediated chemoresistance in small cell lung cancer. (2012)
  • Author(s): Minami T, Kijima T, Otani Y, Kohmo S, Takahashi R, Nagatomo I, Hirata H, Suzuki M, Inoue K, Takeda Y, Kida H, Tachibana I, Kumanogoh A
  • Journal Title: Molecular Cancer Therapeutics Volume: 11(4) Issue: 4 Pages: 830-841
  • DOI: 10.1158/1535-7163.mct-11-0884
  • Peer Reviewed
• [Presentation] HER2陽性再発小細胞肺癌に対するirinotecan + trastuzumab併用療法（基礎研究から臨床応用まで） (2014)
  • Author(s): 南 俊行，甲原雄平，木島貴志，森村 治、大塚倫之，三宅浩太郎，竹内美子、井上幸治，長友 泉，木田 博，熊ノ郷 淳
  • 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] EphA2レセプター阻害はセネッセンス誘導を介して小細胞肺がん細胞の増殖を抑制する (2014)
  • Author(s): 森村 治，木島貴志，南 俊行，熊ノ郷 淳
  • Organizer: 第73回 日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Trastuzumab-based chemotherapy for HER2-positive refractory relapsed small-cell lung cancer (from bench to bed side) (2014)
  • Author(s): 甲原雄平，南 俊行，木島貴志，福島清春，葉山善友，竹内美子，平田陽彦，井上幸治，熊ノ郷 淳
  • 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] Targeting HER2 and VEGF stepwise can overcome multidrug resistance in small cell lung cancer. (2014)
  • Author(s): Minami T, Kijima T, Kinehara Y, Morimura O, Higashiguchi M, Miyake K, Hirata H, Takeuchi Y, Fukushima K, Hayama Y, Inoue K, Nagatomo I, Takeda Y, Kida H, Kumanogoh A.
  • Organizer: 第105回 米国癌学会(AACR) 2014
  • Place of Presentation: San Diego、CA, USA
  • Year and Date: 2014-04-05 – 2014-04-09
• [Presentation] 分子標的治療による小細胞肺癌の抗癌剤耐性の克服 (2013)
  • Author(s): 南 俊行、木島貴志、大谷安司
  • Organizer: 第17回日本がん分子標的治療学会学術集会
  • Place of Presentation: 京都
• [Presentation] HER2 as therapeutic target for overcoming ATP-binding cassette transporter-mediated chemoresistance in small cell lung cancer (2012)
  • Author(s): 南 俊行，木島貴志，大谷安司，河面 聡，高橋 良，長友 泉，平田陽彦，鈴木真優美，井上幸治，武田吉人，木田 博，立花 功，熊ノ郷 淳
  • Organizer: 第103回 AACR (Ammerican Association for Cancer Research) annual meeting
  • Place of Presentation: 米国 シカゴ
• [Presentation] Molecular targeting therapy to overcome chemoresistance in small cell lung cancer (2012)
  • Author(s): 南 俊行，木島貴志，河面 聡，大谷安司，高橋 良，長友 泉，武田吉人，立花 功，熊ノ郷 淳
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 北海道 札幌