Mutual exclusiveness of driver oncogenes

• Project/Area Number: 15K14412
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Tumor therapeutics
• Research Institution: Japanese Foundation for Cancer Research
• Principal Investigator: KATAYAMA Ryohei 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, 主任研究員 (60435542)
• Co-Investigator(Renkei-kenkyūsha): 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)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 分子標的治療 / 肺腺がん / がん遺伝子 / 相互排他性 / チロシンキナーゼ / 過剰活性化 / 細胞死 / がん / Driver oncogene

Outline of Final Research Achievements

Along with the progress of genome sequencing with next generation sequencers, genetic abnormalities in cancer have been extensively uncovered. As the results of the comprehensive sequencing of cancer genome, it is known that driver oncogene mutation is mutually exclusive, but its reason has not been covered yet. In this study, we found that the excessively upregulate driver oncogene derived signaling induce cell death instead of cell proliferation using ROS1 fusion oncogene induced cells. We also found the key pathway and molecules which are related to trigger cell death when the driver oncogene signaling became excessive.

Research Products

• [Journal Article] APC mutations as a predictive biomarker for sensitivity to tankyrase inhibitors in colorectal cancer. (2017)
  • Author(s): Noritaka Tanaka, Tetsuo Mashima, Anna Mizutani, Ayana Sato, Aki Aoyama, Bo Gong, Haruka Yoshida, Yukiko Muramatsu, Kento Nakata, Masaaki Matsuura, Ryohei Katayama, Satoshi Nagayama, Naoya Fujita, Yoshikazu Sugimoto, Hiroyuki Seimiya
  • Journal Title: Mol. Cancer Ther. Volume: 16 Issue: 4 Pages: 739-751
  • DOI: 10.1158/1535-7163.mct-16-0578
  • Peer Reviewed / Open Access
• [Journal Article] Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutated non-small-cell lung cancer. (2017)
  • Author(s): Ken Uchibori, Naohiko Inase, Mitsugu Araki, Mayumi Kamada, Shigeo Sato, Yasushi Okuno, Naoya Fujita, Ryohei Katayama
  • Journal Title: Nature Commun. Volume: 8 Issue: 1 Pages: 14768-14768
  • DOI: 10.1038/ncomms14768
  • NAID: 120006027079
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Therapeutic strategies and mechanisms of drug resistance in anaplastic lymphoma kinase (ALK)-rearranged lung cancer. (2017)
  • Author(s): Katayama R
  • Journal Title: Pharmacology & Therapeutics Volume: in press Pages: 1-8
  • DOI: 10.1016/j.pharmthera.2017.02.015
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer. (2016)
  • Author(s): Gainor JF, Dardaei L, Yoda S, Friboulet L, Leshchiner I, Katayama R, Engelman JA, Shaw AT, et al.
  • Journal Title: Cancer Discovery Volume: 6 Issue: 10 Pages: 1118-1133
  • DOI: 10.1158/2159-8290.cd-16-0596
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] P-glycoprotein mediates ceritinib resistance in anaplastic lymphoma kinase-rearranged non-small cell lung cancer. (2016)
  • Author(s): Katayama R*, Sakashita T, Yanagitani N, Ninomiya H, Horiike A, Friboulet L, Gainor JF, Motoi N, Dobashi A, Sakata S, Tambo Y, Kitazono S, Sato S, Koike S, Iafrate AJ, Mino-Kenudson M, Ishikawa Y, Shaw AT, Engelman JA, Takeuchi K, Nishio M*, Fujita N*
  • Journal Title: EBioMedicine Volume: 3 Pages: 54-66
  • DOI: 10.1016/j.ebiom.2015.12.009
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Therapeutic targeting of anaplastic lymphoma kinase in lung cancer: a paradigm for precision cancer medicine. (2015)
  • Author(s): Katayama R*, Lovly CM, Shaw AT
  • Journal Title: Clinical Cancer Research Volume: 21 Issue: 10 Pages: 2227-2235
  • DOI: 10.1158/1078-0432.ccr-14-2791
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Inhibitor deprivation mediated excessive oncogene signaling in drug resistant cancers induces both growth and apoptosis signaling. (2017)
  • Author(s): Hayato Ogura, Jun Adachi, Takeshi Tomonaga, Naoya Fujita, Ryohei Katayama
  • Organizer: AACR 2017
  • Place of Presentation: ワシントン, 米国
  • Year and Date: 2017-04-01
  • Int'l Joint Research
• [Presentation] ドライバーがん遺伝子陽性がんにおける分子標的薬耐性機構とその検索 (2017)
  • Author(s): 片山量平
  • Organizer: 第1回Liquid Biopsy研究会
  • Place of Presentation: 東京
  • Year and Date: 2017-01-21
  • Invited
• [Presentation] ALK戦線異常アリ：多様なTKI耐性機構とその克服 (2016)
  • Author(s): 片山 量平
  • Organizer: 第57回日本肺癌学会学術集会
  • Place of Presentation: 福岡
  • Year and Date: 2016-12-19
  • Invited
• [Presentation] Tumor cell and stromal cell mediated drug resistance in driver oncogene positive non-small cell lung cance (2016)
  • Author(s): 片山 量平
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
  • Invited
• [Presentation] FGFR3またはcMETの過剰活性化を介したALK阻害薬耐性機構の発見 (2016)
  • Author(s): Ryohei Katayama, Sumie Koike, Tomoko Oh-hara, Makoto Nishio, Naoya Fujita
  • Organizer: 第20回 日本がん分子標的治療学会学術総会
  • Place of Presentation: 大分県別府市
  • Year and Date: 2016-05-30
• [Presentation] 肺がん臨床検体を用いた分子標的薬耐性機構の解明 (2016)
  • Author(s): 片山量平
  • Organizer: 平成27年度「がん研究分野の特性等を踏まえた支援活動」公開シンポジウム
  • Place of Presentation: 東京、学術総合センター
  • Year and Date: 2016-02-09
  • Invited
• [Presentation] ALK阻害薬耐性の分子基盤 (2015)
  • Author(s): 片山量平
  • Organizer: 第56回日本肺癌学会学術集会
  • Place of Presentation: パシフィコ横浜、横浜
  • Year and Date: 2015-11-26
  • Invited
• [Presentation] Novel ceritinib resistance mechanisms: new resistant mutation, fibroblast growth factor receptor 3 overexpression and cMET amplification-mediated ceritinib resistance (2015)
  • Author(s): yohei Katayama, Takuya Sakashita, Noriko Yanagitani, Kengo Takeuchi, Makoto Nishio, Naoya Fujita
  • Organizer: AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics
  • Place of Presentation: 米国、ボストン
  • Year and Date: 2015-11-05
  • Int'l Joint Research
• [Presentation] Resistance mechanisms to molecular targeted therapy in ALK or ROS1 rearranged non-small cell lung cancer (2015)
  • Author(s): 片山 量平
  • Organizer: 第５３回 日本癌治療学会総会
  • Place of Presentation: 京都国際会議場、京都
  • Year and Date: 2015-10-29
  • Invited
• [Presentation] Characterization of the ALK-TKI resistant cells mediated by secondary mutations or bypass pathway activation (2015)
  • Author(s): 小池清恵、坂下卓也、西尾誠人、藤田直也、片山量平
  • Organizer: 第７４回 日本癌学会総会
  • Place of Presentation: 名古屋国際会議場、名古屋
  • Year and Date: 2015-10-09
• [Presentation] Molecular mechanisms of the resistance to ALK- or ROS1-TKIs in ALK or ROS1 rearranged non-small cell lung cancer (2015)
  • Author(s): 片山 量平
  • Organizer: 第７４回 日本癌学会総会
  • Place of Presentation: 名古屋国際会議場、名古屋
  • Year and Date: 2015-10-08
  • Invited
• [Presentation] Molecular mechanism of the TKI resistance in lung cancer ～TKI-resistance in fusion gene driven lung cancer～ (2015)
  • Author(s): 片山 量平
  • Organizer: 第１３回 日本臨床腫瘍学会学術総会
  • Place of Presentation: ロイトン札幌、札幌
  • Year and Date: 2015-07-16
  • Invited
• [Presentation] 培養細胞株と患者検体を用いたALK阻害薬耐性機構の解析 (2015)
  • Author(s): 片山量平、小池清恵、西尾誠人、藤田直也
  • Organizer: 第１９回日本がん分子標的治療学会
  • Place of Presentation: 松山全日空ホテル、愛媛
  • Year and Date: 2015-06-10
• [Remarks] EGFR変異陽性肺がんに対する新規耐性克服療法を発見 ～今後予想されるオシメルチニブ耐性の克服へ～
  • URL: http://www.jfcr.or.jp/laboratory/news/4824.html
• [Remarks] 【プレスリリース】 ALK陽性肺がんに対する治療薬耐性の原因を発見 ～より効果的な治療法の選択へ道～
  • URL: http://www.jfcr.or.jp/chemotherapy/news/4146.html
• [Patent(Industrial Property Rights)] EGFR-TKI耐性を獲得した肺癌の治療薬 (2016)
  • Inventor(s): 片山量平、内堀健、藤田直也
  • Industrial Property Rights Holder: 公益財団法人がん研究会
  • Industrial Property Rights Type: 特許
  • Filing Date: 2016-12-06