Analysis of acquired resistance mechanisms to next-generation kinase inhibitors in lung cancers with EGFR mutation.

• Project/Area Number: 25830119
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor therapeutics
• Research Institution: Kinki University
• Principal Investigator: SUDA Kenichi 近畿大学, 医学部, 助教 (30631593)
• Research Collaborator: MIZUUCHI Hiroshi ; SATO Katsuaki
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 分子標的薬 / 肺癌 / 耐性 / EGFR変異 / 個別化治療 / 分子標的治療 / 獲得耐性 / EGFR遺伝子変異 / 分子標的治療薬

Outline of Final Research Achievements

EGFR kinase inhibitors are the key drugs in the treatment of lung cancer patients with EGFR activating mutations. However, emergence of acquired resistance to these drugs is almost inevitable. There are several unanswered issues to establish best treatment strategies after acquisition of resistance to EGFR kinase inhibitors. These include, (1) if chemosensitivity alters after acquisition of resistance, (2) novel resistance mechanisms other than T790M mutation. MET amplification, ERBB2 amplification, etc, and (3) molecular mechanisms that confer acquired resistance to next-generation EGFR kinase inhibitors. In this work, we analyzed these points, mainly using in vitro models.

Research Products

• [Journal Article] Racial differences in lung cancer genetics. (2015)
  • Author(s): Kenichi Suda, and Tetsuya Mitsudomi
  • Journal Title: Journal of Thoracic Oncology Volume: 10 Issue: 2 Pages: 230-1
  • DOI: 10.1097/jto.0000000000000439
  • Acknowledgement Compliant
• [Journal Article] The insulin-like growth factor 1 receptor causes acquired resistance to erlotinib in lung cancer cells with the wild-type epidermal growth factor receptor. (2014)
  • Author(s): Suda K, Mizuuchi H, Sato K, Takemoto T, Iwasaki T, Mitsudomi T.
  • Journal Title: Int. J. Cancer Volume: in press Issue: 4 Pages: 1002-6
  • DOI: 10.1002/ijc.28737
  • Peer Reviewed
• [Journal Article] CRKL amplification is rare as a mechanism for acquired resistance tokinase inhibitors in lung cancers with epidermal growth factorreceptor mutation (2014)
  • Author(s): Kenichi Suda, Hiroshi Mizuuchi, Isao Murakami, Hidetaka Uramoto,Fumihiro Tanaka, Katsuaki Sato, Toshiki Takemoto, Takuya Iwasaki,Yoshitaka Sekido, Yasushi Yatabe, Tetsuya Mitsudomi
  • Journal Title: Lung Cancer Volume: 85 Pages: 147-51
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Prognostic Implication of Predominant Histologic Subtypes of Lymph Node Metastases in Surgically Resected Lung Adenocarcinoma (2014)
  • Author(s): Kenichi Suda, Katsuaki Sato, Shigeki Shimizu, Kenji Tomizawa, Toshiki Takemoto, Takuya Iwasaki, Masahiro Sakaguchi, and Tetsuya Mitsudomi
  • Journal Title: BioMed Research International Volume: 2014 Pages: 1-6
  • DOI: 10.1155/2014/645681
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Recent evidence, advances, and current practices in surgical treatment of lung cancer (2014)
  • Author(s): Kenichi Suda, Katsuaki Sato, Hiroshi Mizuuchi, Yoshihisa Kobayashi, Masaki Shimoji, Kenji Tomizawa, Toshiki Takemoto, Takuya Iwasaki, Masahiro Sakaguchi, Tetsuya Mitsudomi
  • Journal Title: Respiratory Investigation Volume: 52 Issue: 6 Pages: 322-9
  • DOI: 10.1016/j.resinv.2014.06.003
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Unintentional Weakness of Cancers: The MEK–ERK Pathway as a Double-Edged Sword. (2013)
  • Author(s): Suda K and Mitsudomi T.
  • Journal Title: Molecular Cancer Research Volume: 11 Issue: 10 Pages: 1125-8
  • DOI: 10.1158/1541-7786.mcr-13-0228
  • Peer Reviewed
• [Journal Article] Development of personalized treatments in lung cancer: focusing on the EGFR mutations and beyond. (2013)
  • Author(s): Suda K and Mitsudomi T.
  • Journal Title: Lung Cancer: Targets and THerapy Volume: 4 Pages: 43-53
  • DOI: 10.2147/lctt.s49603
  • Peer Reviewed
• [Presentation] 肺腺癌新国際分類によるリンパ節転移巣の再評価とその臨床的意義 (2014)
  • Author(s): 須田健一、 佐藤克明、 清水重喜、 水内寛、 小林祥久、 下治正樹、 富沢健二、 武本智樹、 岩崎拓也、 阪口全宏、 光冨徹哉
  • Organizer: 第55回日本肺癌学会学術集会
  • Place of Presentation: 京都（国立京都国際会館）
  • Year and Date: 2014-11-14 – 2014-11-16
• [Presentation] Reciprocal relationship between EGFR T790M mutation and small cell lung cancer transformation as acquired resistance molecular mechanisms to EGFR kinase inhibitor (2014)
  • Author(s): Kenichi Suda, Katsuaki Sato, Isao Murakami, Hiroshi Mizuuchi, Kazuko Sakai, Shuta Tomida, Shigeki Shimizu, Yoshihisa Kobayashi, Masaki Shimoji, Kenji Tomizawa, Toshiki Takemoto, Takuya Iwasaki, Masahiro Sakaguchi, Kazuto Nishio, Yasushi Yatabe, and Tetsuya Mitsudomi
  • Organizer: 6th Asia Pacific Lung Cancer Conference
  • Place of Presentation: Kuala Lumpur（Shangri-La Hotel）
  • Year and Date: 2014-11-06 – 2014-11-08
• [Presentation] 肺腺癌新国際分類からみたリンパ節転移巣の再評価とその臨床的意義 (2014)
  • Author(s): 須田健一、 佐藤克明、 清水重喜、 水内寛、 小林祥久、 下治正樹、 富沢健二、 武本智樹、 岩崎拓也、 阪口全宏、 光冨徹哉
  • Organizer: 第67回日本胸部外科学会定期学術集会
  • Place of Presentation: 福岡（福岡国際会議場、福岡サンパレスホテル＆ホール）
  • Year and Date: 2014-09-30 – 2014-10-03
• [Presentation] Molecular and pathological evolution in acquisition of resistance to EGFR-TKI - T790M mutation and SCLC transformation- (2014)
  • Author(s): Kenichi Suda, Isao Murakami, Katsuaki Sato, Shuta Tomida, Hiroshi Mizuuchi, Kazuko Sakai, Shigeki Shimizu, Kenji Tomizawa, Toshiki Takemoto, Masahiro Sakaguchi, Kazuto Nishio, Yasushi Yatabe, and Tetsuya Mitsudomi
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜（パシフィコ横浜）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] EGFR野生型肺癌におけるエルロチニブ獲得耐性機序の探索 (2014)
  • Author(s): 須田健一、 水内寛、 佐藤克明、 武本智樹、 岩崎拓也、 南憲司、 阪口全宏、 光冨徹哉
  • Organizer: 第114回日本外科学会定期学術集会
  • Place of Presentation: 京都（国立京都国際会館、グランドプリンスホテル京都）
  • Year and Date: 2014-04-03 – 2014-04-05
• [Presentation] EGFR野生型肺癌におけるエルロチニブ獲得耐性機序の探索 (2014)
  • Author(s): 須田健一、水内寛、佐藤克明、武本智樹、岩崎拓也、南憲司、光冨徹哉
  • Organizer: 第114回日本外科学会定期学術集会
  • Place of Presentation: 京都
• [Presentation] In vitro analysis of acquired resistance mechanisms to EGFR tyrosine kinase inhibitors in lung cancer (2014)
  • Author(s): Suda K, Mizuuchi H, Sato K, Takemoto T, Iwasaki T, Minami K, Mitsudomi T
  • Organizer: 2nd International Symposium of Training Plan for Oncology Professionals
  • Place of Presentation: Osaka
  • Invited
• [Presentation] Several receptor tyrosine kinase is activated but orchestrated by EGFR in EGFR-TKI acquired resistant lung adenocarcinoma cells with EGFR mutation (2013)
  • Author(s): Suda K, Mizuuchi H, Sato K, Takemoto T, Iwasaki T, Minami K, Yatabe Y, Mitsudomi T
  • Organizer: 15th World Conference on Lung Cancer
  • Place of Presentation: Sydney
• [Presentation] 臨床検体より樹立したゲフィチニブ獲得耐性細胞株の解析 (2013)
  • Author(s): 須田健一、伊藤志門、水内寛、武本智樹、岩崎拓也、南憲司、谷田部恭、光冨徹哉
  • Organizer: 第54回日本肺癌学会総会
  • Place of Presentation: 東京
• [Book] PTEN - Structure, Mechanisms-of-Action, Role in Cell Signaling and Regulation (2013)
  • Author(s): Suda K, et al.
  • Total Pages: 265
  • Publisher: NOVA BIOMEDICAL