• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Molecular analysis of EGFR-TKI resistance and development of overcoming drugs

Research Project

Project/Area Number 24300344
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypePartial Multi-year Fund
Section一般
Research Field Clinical oncology
Research InstitutionJapanese Foundation for Cancer Research

Principal Investigator

FUJITA Naoya  公益財団法人がん研究会, がん化学療法センター, 所長 (20280951)

Research Collaborator SATO Shigeo  
KATAYAMA Ryohei  
OH-HARA Tomoko  
TAKAMI Miho  
KOIKE Sumie  
NODA Sachie  
AOYAMA Aki  
MIYATA Kenichi  
KOBAYASHI Yuka  
SAKASHITA Takuya  
HIRAIAWA Yukari  
TAKATORI Kazuki  
FUSE Miho Jane  
Project Period (FY) 2012-04-01 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
Budget Amount *help
¥19,370,000 (Direct Cost: ¥14,900,000、Indirect Cost: ¥4,470,000)
Fiscal Year 2014: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
Fiscal Year 2013: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2012: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Keywordsがん化学療法 / 分子標的治療 / 併用療法 / EGFR / ALK / 癌 / EGFR-TKI / MET / c-Met
Outline of Final Research Achievements

In this project, we tried to analyze the mechanisms of EGFR-TKI and ALK-TKI resistance and to develop overcoming drugs. We performed the following experiments and obtained several new findings.
(1) We searched the EGFR binding protein and found that Aki1, a scaffold protein, interacted with EGFR and mediated EGFR-TKI resistance. We could not find out the positive relationship between Pim kinase expression and EGFR-TKI resistance. During the analysis of c-met signaling pathway for EGFR-TKI resistance, we found that a c-met inhibitor tivantinib, exhibited anti-tumor activity by inhibiting tubulin polymerization.
(2) Using patient-derived samples, we succeeded to identify several mutations that were associated with ALK-TKI resistance. Theese resistance could be overcame the second generation ALK-TKIs, such as alectinib and ceritinib.

Report

(4 results)
  • 2014 Annual Research Report   Final Research Report ( PDF )
  • 2013 Annual Research Report
  • 2012 Annual Research Report

Research Products

(31 results)

All 2015 2014 2013 2012 Other

All Journal Article (9 results) (of which Peer Reviewed: 9 results,  Acknowledgement Compliant: 4 results) Presentation (19 results) (of which Invited: 2 results) Remarks (3 results)

  • [Journal Article] Two novel ALK mutations mediate acquired resistance to the next-generation ALK inhibitor alectinib.2014

    • Author(s)
      Ryohei Katayama, Luc Friboulet, Sumie Koike, Elizabeth L. Lockerman, Tahsin M. Khan, Justin F. Gainor, A. John Iafrate, Kengo Takeuchi, Makoto Taiji, Yasushi Okuno, Naoya Fujita, Jeffrey A. Engelman, Alice T. Shaw
    • Journal Title

      Clinical Cancer Research

      Volume: 20 Pages: 5686-5696

    • DOI

      10.1158/1078-0432.ccr-14-1511

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Tivantinib (ARQ 197) exhibits antitumor activity by directly interacting with tubulin and overcomes ABC transporter–mediated drug resistance.2014

    • Author(s)
      Aki Aoyama, Ryohei Katayama, Tomoko Oh-hara, Shigeo Sato, Yasushi Okuno and Naoya Fujita
    • Journal Title

      Molecular Cancer Therapeutics

      Volume: 13 Pages: 2978-2990

    • DOI

      10.1158/1535-7163.mct-14-0462

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Expression of Akt kinase-interacting protein 1, a scaffold protein of the PI3K/PDK1/Akt pathway, in pancreatic cancer.2014

    • Author(s)
      Ohtsubo K, Yano S, et al.
    • Journal Title

      Pancreas

      Volume: 43 Pages: 1093-100

    • DOI

      10.1097/mpa.0000000000000168

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer.2014

    • Author(s)
      Friboulet L, Li N, Katayama R, Lee CC, Gainor JF, Crystal AS, Michellys PY, Awad MM, Yanagitani N, Kim S, Pferdekamper AC, Li J, Kasibhatla S, Sun F, Sun X, Hua S, McNamara P, Mahmood S, Lockerman EL, Fujita N, Nishio M, Harris JL, Shaw AT, Engelman JA
    • Journal Title

      Cancer Discovery

      Volume: 4 Pages: 662-673

    • DOI

      10.1158/2159-8290.cd-13-0846

    • Related Report
      2014 Annual Research Report 2013 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] The mERG1a channel modulates skeletal muscle MuRF1, but not MAFbx, expression.2014

    • Author(s)
      Pond AL, Nedele C, Wang WH, Wang X, Walther C, Jaeger C, Bradley KS, Du H, Fujita N, Hockerman GH, Hannon KM.
    • Journal Title

      Muscle Nerve

      Volume: 49 Pages: 378-388

    • DOI

      10.1002/mus.23924

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cytotoxic Activity of Tivantinib (ARQ 197) Is Not Due Solely to c-MET Inhibition2013

    • Author(s)
      Katayama R, Aoyama A, Yamori T, Qi J, Oh-Hara T, Song Y, Engelman JA, Fujita N
    • Journal Title

      Cancer Res.

      Volume: 73(10) Pages: 3087-3096

    • DOI

      10.1158/0008-5472.can-12-3256

    • Related Report
      2013 Annual Research Report 2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Akt kinase-interacting protein1, a novel therapeutic target for lung cancer with EGFR activating and gatekeeper mutations.2013

    • Author(s)
      Yamada T, Yano S, et al.
    • Journal Title

      Oncogene

      Volume: 32 Pages: 4427-35

    • DOI

      10.1038/onc.2012.446

    • NAID

      120004997024

    • Related Report
      2013 Annual Research Report 2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Downregulation of AKT reverses platinum resistance of human ovarian cancers in vitro2012

    • Author(s)
      Jens Hahne
    • Journal Title

      Oncology Reports

      Volume: 28 Pages: 2023-2028

    • DOI

      10.3892/or.2012.2041

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Successive phosphorylation of p27^<KIP1> protein at serine-10 and C terminus crucially controls its potency to inactivate Cdk2.2012

    • Author(s)
      Atish R. Mohanty
    • Journal Title

      Journal of Biological Chemistry

      Volume: 287 Pages: 21757-21764

    • DOI

      10.1074/jbc.m112.346254

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Presentation] ALK阻害薬への耐性とその克服2015

    • Author(s)
      藤田直也
    • Organizer
      日本癌学会シンポジウム/共同利用・共同研究拠点シンポジウム
    • Place of Presentation
      石川県立音楽堂交流ホール、金沢
    • Year and Date
      2015-01-21 – 2015-01-22
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] Acquired resistance in ALK rearranged NSCLC: Mechanisms of and strategies to overcome resistance2014

    • Author(s)
      片山量平、藤田直也
    • Organizer
      第73回日本癌学会総会
    • Place of Presentation
      パシフィコ横浜、横浜
    • Year and Date
      2014-09-25 – 2014-09-27
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] New resistance mechanisms to second-generation ALK inhibitor Ceritinib (LDK378)2014

    • Author(s)
      坂下卓矢、片山量平、藤田直也
    • Organizer
      第73回日本癌学会総会
    • Place of Presentation
      パシフィコ横浜、横浜
    • Year and Date
      2014-09-25 – 2014-09-27
    • Related Report
      2014 Annual Research Report
  • [Presentation] Identification of the alectinib-resistance mechanism in NSCLC harboring ALK rearrangement2014

    • Author(s)
      小池清恵、片山量平、藤田直也
    • Organizer
      第73回日本癌学会総会
    • Place of Presentation
      パシフィコ横浜、横浜
    • Year and Date
      2014-09-25 – 2014-09-27
    • Related Report
      2014 Annual Research Report
  • [Presentation] Identification of and overcoming the crizotinib and ceritinib resistance in ROS1-rearranged lung cancers2014

    • Author(s)
      小林由佳、片山量平、藤田直也
    • Organizer
      第73回日本癌学会総会
    • Place of Presentation
      パシフィコ横浜、横浜
    • Year and Date
      2014-09-25 – 2014-09-27
    • Related Report
      2014 Annual Research Report
  • [Presentation] Tivantinib (ARQ197) shows antitumor activity by reduced tubulin polymerization and overcomes tubulin binder-resistance2014

    • Author(s)
      青山暁、片山量平、藤田直也
    • Organizer
      第73回日本癌学会総会
    • Place of Presentation
      パシフィコ横浜、横浜
    • Year and Date
      2014-09-25 – 2014-09-27
    • Related Report
      2014 Annual Research Report
  • [Presentation] 膵癌における新規足場蛋白Akt kinase-interacting protein 1 (Aki1) の発現2014

    • Author(s)
      大坪公士郎, 藤田直也、矢野聖二
    • Organizer
      第45回日本膵臓学会大会
    • Place of Presentation
      北九州国際会議場、北九州
    • Year and Date
      2014-07-11 – 2014-07-12
    • Related Report
      2014 Annual Research Report
  • [Presentation] Therapeutic strategies to overcome the crizotinib resistance in ROS1-rearranged lung cancers.2014

    • Author(s)
      Ryohei Katayama, Yuka Kobayashi, Sumie Koike, Naoya Fujita
    • Organizer
      Annual Meeting of the American Association for Cancer Research
    • Place of Presentation
      San Diego, CA, USA
    • Year and Date
      2014-04-05 – 2014-04-09
    • Related Report
      2014 Annual Research Report
  • [Presentation] Antitumor activity of tivantinib (ARQ 197) is due to disruption of microtubule assembly in addition to c-MET inhibition.2013

    • Author(s)
      Aki Aoyama, Ryohei Katayama, Takao Yamori, Jie Qi, Tomoko Oh-hara, Youngchul Song, Jeffrey A. Engelman and Naoya Fujita
    • Organizer
      The 18th International Symposium on Cancer Chemotherapy
    • Place of Presentation
      未来館ホール、東京
    • Related Report
      2013 Annual Research Report
  • [Presentation] Induction of synergy suppression by combination of kinase inhibitors using ALK inhibitor resistant cell lines2013

    • Author(s)
      赤松香奈子、片山量平、田中義久、藤田直也、奥野恭史
    • Organizer
      第36回日本分子生物学会年会
    • Place of Presentation
      神戸ポートアイランド、神戸
    • Related Report
      2013 Annual Research Report
  • [Presentation] Patterns of relapse and prognosis after Crizotinib therapy failure in ALK+ Non-small cell lung cancer.2013

    • Author(s)
      Noriko Yanagitani, Hironari Nishizawa, Ryohei Katayama, Hiroshi Kobayashi, Hiroshi Gyoutoku, Takeshi Uenami, Yuichi Tambo, Keita Kudo, Fumiyoshi Ohyanagi, Atsushi Horiike, Hironori Ninomiya, Noriko Motoi, Kengo Takeuchi, Yuichi Ishikawa, Naoya Fujita, Takeshi Horai, Makoto Nishio.
    • Organizer
      15th World Conference on Lung Cancer
    • Place of Presentation
      Sydney, Australia
    • Related Report
      2013 Annual Research Report
  • [Presentation] Cytotxic Activity of Tivantinib (ARQ197) is not due solely to c-MET inhibition2013

    • Author(s)
      片山量平, 大原智子, 矢守隆夫, 藤田直也
    • Organizer
      第72回 日本癌学会総会
    • Place of Presentation
      パシフィコ横浜、横浜
    • Related Report
      2013 Annual Research Report
  • [Presentation] Identification of the 2nd generation ALK inhibitor-resistance mechanism in NSCLC harboring EML4-ALK2013

    • Author(s)
      小池清恵, 片山量平, 藤田直也
    • Organizer
      第72回 日本癌学会総会
    • Place of Presentation
      パシフィコ横浜、横浜
    • Related Report
      2013 Annual Research Report
  • [Presentation] キナーゼ阻害薬とその耐性化機構2013

    • Author(s)
      藤田直也
    • Organizer
      第17回日本がん分子標的治療研究会
    • Place of Presentation
      国立京都国際会館、京都
    • Related Report
      2013 Annual Research Report
  • [Presentation] Tivantinib(ARQ197)の抗腫瘍効果に関わる新規分子標的の同定2013

    • Author(s)
      青山暁、片山量平、矢守隆夫、大原智子、藤田直也
    • Organizer
      第17回日本がん分子標的治療研究会
    • Place of Presentation
      国立京都国際会館、京都
    • Related Report
      2013 Annual Research Report
  • [Presentation] 新規足場蛋白Aki1を標的としたEGFR遺伝子変異陽性肺がんの制御2013

    • Author(s)
      山田忠明、竹内伸司、藤田直也、矢野聖二
    • Organizer
      第17回日本がん分子標的治療研究会
    • Place of Presentation
      国立京都国際会館、京都
    • Related Report
      2013 Annual Research Report
  • [Presentation] Antitumor activity of Tivantinib (ARQ 197) is due to inhibition of tubulin polymerization in addition to c-Met inhibition.2013

    • Author(s)
      Ryohei Katayama, Aki Aoyama, Takao Yamori, Jie Qi, Tomoko Oh-hara, Youngchul Song, Jeffrey A. Engelman, Naoya Fujita
    • Organizer
      The 104th Annual Meeting of the American Association for Cancer Research
    • Place of Presentation
      Washington, DC, USA
    • Related Report
      2013 Annual Research Report
  • [Presentation] Akt kinase-interacting protein1, a novel therapeutic target for lung cancer with EGFR activating mutations2012

    • Author(s)
      Tadaaki Yamada
    • Organizer
      第71回 日本癌学会総会
    • Place of Presentation
      ロイトン札幌、札幌
    • Year and Date
      2012-09-19
    • Related Report
      2012 Annual Research Report
  • [Presentation] キナーゼ阻害薬(Year in Review)2012

    • Author(s)
      Naoya Fujita
    • Organizer
      第16回日本がん分子標的治療学会
    • Place of Presentation
      西日本総合展示場、北九州
    • Year and Date
      2012-06-28
    • Related Report
      2012 Annual Research Report
  • [Remarks] 公益財団法人がん研究会がん化学療法センター基礎研究部ホームページ

    • URL

      http://www.jfcr.or.jp/chemotherapy/department/fundamental/index.html

    • Related Report
      2014 Annual Research Report
  • [Remarks] 研究代表者の研究室HP

    • URL

      http://www.jfcr.or.jp/chemotherapy/department/fundamental/index.html

    • Related Report
      2013 Annual Research Report
  • [Remarks]

    • URL

      http://www.jfcr.or.jp/chemotherapy/department/fundamental/index.html

    • Related Report
      2012 Annual Research Report

URL: 

Published: 2012-04-23   Modified: 2019-07-29  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi