A biomarker study of heregulin to predict efficacy of anti-HER2 drugs in HER2-positive breast and gastric cancer

• Project/Area Number: 26430174
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: Kindai University
• Principal Investigator: TSURUTANI Junji 近畿大学, 医学部, 准教授 (30319686)
• Co-Investigator(Kenkyū-buntansha): 中川 和彦 近畿大学, 医学部, 教授 (40298964) ; 米阪 仁雄 近畿大学, 医学部附属病院, 講師 (30330260)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: HER2 / 乳癌 / 胃癌 / 化学療法 / 分子標的薬 / 薬剤耐性 / ヘレギュリン / 西日本がん研究機構 / WJOG7212G / cfDNA BC / N87 / SKBR-3 / 血漿検体 / heregulin / 分子標的治療

Outline of Final Research Achievements

Recombinant heregulin desensitized HER2 positive breast or gastric cancer cell lines to trastuzumab, lapatinib, but not to T-DM1. The SKBR3 and N87 cells were transfected with heregulin gene and sensitivities of those cell to each drug were evaluated. The transfectants were desensitized to trastuzumab and lapatinib, but not T-DM1. The resuls were likewise in the xenograft model innoculated with the heregulin-transfected N87 cells. In clinical specimens obtained from patinets with breast or gastric cancer who became resistant to trastuzumab, the expression levels of heregulin protein were upregulated compared to the pre-treatment samples, suggesting that heregulin is involved in the acquired resistance to anti-HER2 therapy, other than T-DM1.

Research Products

• [Journal Article] [fam‐] trastuzumab deruxtecan, antitumor activity is dependent on HER2 expression level rather than on HER2 amplification (2019)
  • Author(s): Takegawa Naoki、Tsurutani Junji、Kawakami Hisato、Yonesaka Kimio、Kato Ryoji、Haratani Koji、Hayashi Hidetoshi、Takeda Masayuki、Nonagase Yoshikane、Maenishi Osamu、Nakagawa Kazuhiko
  • Journal Title: International Journal of Cancer Volume: 145 Issue: 12 Pages: 3414-3424
  • DOI: 10.1002/ijc.32408
  • Peer Reviewed
• [Journal Article] Targeting of the HER2/HER3 signaling axis overcomes ligand-mediated resistance to trastuzumab in HER2-positive breast cancer (2019)
  • Author(s): Satomi Watanabe, Kimio Yonesaka, Junko Tanizaki, Yoshikane Nonagase, Naoki Takegawa, Koji Haratani, Hisato Kawakami, Hidetoshi Hayashi, Masayuki Takeda, Junji Tsurutani, Kazuhiko Nakagawa
  • Journal Title: Cancer Medicine Volume: 8 Issue: 3 Pages: 1258-1268
  • DOI: 10.1002/cam4.1995
  • Peer Reviewed / Open Access
• [Journal Article] Mutational activation of the epidermal growth factor receptor down-regulates major histocompatibility complex class I expression via the extracellular signal-regulated kinase in non-small cell lung cancer (2018)
  • Author(s): Satomi Watanabe, Hidetoshi Hayashi, Koji Haratani, Shigeki Shimizu, Junko Tanizaki, Kazuko Sakai, Hisato Kawakami, Kimio Yonesaka, Junji Tsurutani, Yosuke Togashi, Kazuto Nishio, Akihiko Ito, Kazuhiko Nakagawa
  • Journal Title: Cancer Science Volume: 110 Issue: 1 Pages: 52-60
  • Peer Reviewed / Open Access
• [Journal Article] HER2 genomic amplification in circulating tumor DNA and estrogen receptor positivity predict primary resistance to trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer. (2018)
  • Author(s): Sakai H, Tsurutani J, Iwasa T, Komoike Y, Sakai K, Nishio K, Nakagawa K.
  • Journal Title: Breast Cancer Volume: 25(5) Issue: 5 Pages: 605-613
  • DOI: 10.1007/s12282-018-0861-9
  • Peer Reviewed / Open Access
• [Journal Article] DS-8201a, a new HER2-targeting antibody-drug conjugate incorporating a novel DNA topoisomerase I inhibitor, overcomes HER2-positive gastric cancer T-DM1 resistance (2017)
  • Author(s): Naoki Takegawa, Yoshikane Nonagase, Kimio Yonesaka, Kazuko Sakai, Osamu Maenishi, Yusuke Ogitani, Takao Tamura, Kazuto Nishio, Kazuhiko Nakagawa, Junji Tsurutani
  • Journal Title: International Journal of Cancer Volume: 141 Issue: 8 Pages: 1682-1689
  • DOI: 10.1002/ijc.30870
  • Peer Reviewed / Open Access
• [Journal Article] Heregulin-expressing HER2-positive breast and gastric cancer exhibited heterogeneous susceptibility to the anti-HER2 agents lapatinib, trastuzumab and T-DM1. (2016)
  • Author(s): Nonagase Y, Yonesaka K, Kawakami H, Watanabe S, Haratani K, Takahama T, Takegawa N, Ueda H, Tanizaki J, Hayashi H, Yoshida T, Takeda M, Chiba Y, Tamura T, Nakagawa K, Tsurutani J.
  • Journal Title: Oncotarget Volume: 20;7(51) Issue: 51 Pages: 84860-84871
  • DOI: 10.18632/oncotarget.12743
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] HER2 genomic amplification in circulating tumor DNA from patients with cetuximab-resistant colorectal cancer (2016)
  • Author(s): Naoki Takegawa, Kimio Yonesaka, Kazuko Sakai, Hiroto Ueda, Satomi Watanabe, Yoshikane Nonagase, Tatsuya Okuno, Masayuki Takeda, Osamu Maenishi, Junji Tsurutani, Taroh Satoh, Isamu Okamoto, Kazuto Nishio, Takao Tamura, Kazuhiko Nakagawa
  • Journal Title: Oncotarget Volume: 7 Issue: 3 Pages: 3453-3460
  • DOI: 10.18632/oncotarget.6498
  • Peer Reviewed / Open Access
• [Journal Article] Synergistic antitumor effects of S-1 with eribulin in vitro and in vivo for triple-negative breast cancer cell lines. (2014)
  • Author(s): Terashima M, Sakai K, Togashi Y, Hayashi H, De Velasco MA, Tsurutani J, Nishio K.
  • Journal Title: Springerplus Volume: 3 Issue: 1 Pages: 417-417
  • DOI: 10.1186/2193-1801-3-417
  • Peer Reviewed / Open Access
• [Presentation] heregulin発現HER2陽性乳癌・胃癌における抗HER2薬ラパチニブ、トラスツズマブ、T-DM1の感受性に関する研究 (2017)
  • Author(s): 野長瀬 祥兼, 米阪 仁雄, 川上 尚人, 渡邉 諭美, 原谷 浩司, 高濱 隆幸, 武川 直樹, 植田 勲人, 谷崎 潤子, 林 秀敏, 吉田 健史, 武田 真幸, 千葉 康敬, 田村 孝雄, 中川 和彦, 鶴谷 純司
  • Organizer: 第25回日本乳癌学会総会
• [Presentation] T-DM1 de novo 耐性HER2陽性乳癌の臨床病理学的検討 (2017)
  • Author(s): 酒井 瞳, 岩朝 勤, 菰池 佳史, 鶴谷 純司, 坂井 和子, 西尾 和人, 中川 和彦
  • Organizer: 第25回日本乳癌学会総会
• [Presentation] Heregulin-induced resisitance agatinst HER2-targeted therapies in HER2-positive breast cancer and gastric cancer in vitro and in vivo (2016)
  • Author(s): Nonagase Y, Tsurutani J, et al.
  • Organizer: American Association for Cancer Reserch
  • Place of Presentation: Ernest N. Morial Convention Center(米国、ニューオリンズ)
  • Year and Date: 2016-04-16
  • Int'l Joint Research
• [Presentation] 乳腺個別化医療を拓くバイオマーカー研究HER2陽性乳癌個別化治療の近未来-双方修正にて加筆(11/16昭和大学松山様) (2016)
  • Author(s): 鶴谷純司
  • Organizer: 第24回日本乳癌学会総会
  • Invited
• [Presentation] Heregulin-induced resisitance agatinst HER2-targeted therapies in HER2-positive breast cancer and gastric cancer in vitro and in vivo2016 (2016)
  • Author(s): Yoshikane Nonagase, Junji Tsurutani, et al.
  • Organizer: Annual meeting, American Association of Cancer Research双方修正にて加筆(11/16昭和大学松山様)
  • Int'l Joint Research
• [Book] 新臨床腫瘍学 改訂第4版 (2017)
  • Author(s): 鶴谷純司
  • Total Pages: 840
  • Publisher: 南江堂