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

• Project/Area Number: 24300344
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Clinical oncology
• Research Institution: Japanese 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: ¥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.

Research Products

• [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: Clin. Cancer Res. Volume: 20 Issue: 22 Pages: 5686-5696
  • DOI: 10.1158/1078-0432.ccr-14-1511
  • 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: Mol. Cancer Ther. Volume: 13 Issue: 12 Pages: 2978-2990
  • DOI: 10.1158/1535-7163.mct-14-0462
  • 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 Issue: 7 Pages: 1093-100
  • DOI: 10.1097/mpa.0000000000000168
  • 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 Discov. Volume: 4 Issue: 6 Pages: 662-673
  • DOI: 10.1158/2159-8290.cd-13-0846
  • Peer Reviewed
• [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 Issue: 3 Pages: 378-388
  • DOI: 10.1002/mus.23924
  • Peer Reviewed
• [Journal Article] Cytotoxic Activity of Tivantinib (ARQ 197) Is Not Due Solely to c-MET Inhibition (2013)
  • 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) Issue: 10 Pages: 3087-96
  • DOI: 10.1158/0008-5472.can-12-3256
  • 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 Issue: 37 Pages: 4427-35
  • DOI: 10.1038/onc.2012.446
  • NAID: 120004997024
  • Peer Reviewed
• [Journal Article] Downregulation of AKT reverses platinum resistance of human ovarian cancers in vitro (2012)
  • Author(s): Jens Hahne
  • Journal Title: Oncology Reports Volume: 28 Issue: 6 Pages: 2023-2028
  • DOI: 10.3892/or.2012.2041
  • 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 Issue: 26 Pages: 21757-21764
  • DOI: 10.1074/jbc.m112.346254
  • 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
  • Invited
• [Presentation] Acquired resistance in ALK rearranged NSCLC: Mechanisms of and strategies to overcome resistance (2014)
  • 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
  • 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
• [Presentation] Identification of the alectinib-resistance mechanism in NSCLC harboring ALK rearrangement (2014)
  • 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
• [Presentation] Identification of and overcoming the crizotinib and ceritinib resistance in ROS1-rearranged lung cancers (2014)
  • 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
• [Presentation] Tivantinib (ARQ197) shows antitumor activity by reduced tubulin polymerization and overcomes tubulin binder-resistance (2014)
  • 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
• [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
• [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
• [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
• [Presentation] Induction of synergy suppression by combination of kinase inhibitors using ALK inhibitor resistant cell lines (2013)
  • 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
• [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
• [Presentation] Cytotxic Activity of Tivantinib (ARQ197) is not due solely to c-MET inhibition (2013)
  • 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
• [Presentation] Identification of the 2nd generation ALK inhibitor-resistance mechanism in NSCLC harboring EML4-ALK (2013)
  • 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
• [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
• [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
• [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
• [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
• [Presentation] Akt kinase-interacting protein1, a novel therapeutic target for lung cancer with EGFR activating mutations (2012)
  • 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
• [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
• [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
• [Remarks] 研究代表者の研究室HP
  • URL: http://www.jfcr.or.jp/chemotherapy/department/fundamental/index.html
• [Remarks]
  • URL: http://www.jfcr.or.jp/chemotherapy/department/fundamental/index.html