Resistance mechanisms to molecular targeted drugs in lung adenocarcinoma

• Project/Area Number: 25710015
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Partial 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, その他部局等, 主任研究員 (60435542)
• Co-Investigator(Renkei-kenkyūsha): NISHIO Makoto 公益財団法人がん研究会, 有明病院・呼吸器内科, 部長 (00281593) ; YANAGITANI Noriko 公益財団法人がん研究会, 有明病院・呼吸器内科, 医長 (60400785) ; KITAZONO Satoru 公益財団法人がん研究会, 有明病院・呼吸器内科, 副医長 (90527863)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥25,740,000 (Direct Cost: ¥19,800,000、Indirect Cost: ¥5,940,000); Fiscal Year 2015: ¥7,670,000 (Direct Cost: ¥5,900,000、Indirect Cost: ¥1,770,000); Fiscal Year 2014: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000); Fiscal Year 2013: ¥10,530,000 (Direct Cost: ¥8,100,000、Indirect Cost: ¥2,430,000)
• Keywords: 分子標的薬 / 獲得耐性 / 変異 / チロシンキナーゼ阻害薬 / ALK / 耐性機構 / 遺伝子変異 / ABCトランスポーター / 肺がん / 耐性 / ROS / RET / EGFR / 分子標的治療薬 / ROS1

Outline of Final Research Achievements

Non-small cell lung cancer (NSCLC) harboring driver oncogene such as EGFR mutation, ALK-, ROS1-, rearrangements are exquisitely sensitive to small molecule tyrosine kinase inhibitors (TKIs). Although most these driver oncogene positive NSCLC marketly respond to the corresponding TKIs, cancers inevitably develop resistance within a few years by the multiple mechanisms. We explored the resistance mechanisms to TKIs using cell line models and the patient derived specimens. As the results, we succeded to identify and reported various TKI resistance mechanisms in ALK, ROS1 or other driver oncogene positive NSCLC, such as multiple secondary mutations in the kinase domain, bypass pathway activation, or P-glycoprotein overexpression mediated resistance. We also found the potential therapeutic strategies to overcome the resistances. Our study potentially could serve as a framework for selecting and prioritizing therapeutic strategy in the clinic.

Research Products

• [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] Crizotinib Resensitization by the Lorlatinib ALK L1198F Resistance Mutation. (2016)
  • Author(s): Shaw AT, Friboulet L, Leshchiner I, Gainor JF, Bergqvist S, Brooun A, Burke BJ, Deng YL, Liu W, Dardaei L, Frias RL, Schultz KR, Logan J, James LP, Smeal T, Timofeevski S, Katayama R, Iafrate AJ, Le L, McTigue M, Getz G, Johnson TW, Engelman JA.
  • Journal Title: New Engl J Med Volume: 374 Issue: 1 Pages: 54-61
  • DOI: 10.1056/nejmoa1508887
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] PF-06463922, an ALK/ROS1 Inhibitor, Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models. (2015)
  • Author(s): Zou HY, Friboulet L, Kodack DP, Engstrom LD, Li Q, West M, Tang RW, Wang H, Tsaparikos K, Wang J, Timofeevski S, Katayama R, Dinh DM, Lam H, Lam JL, Yamazaki S, Hu W, Patel B, Bezwada D, Frias RL, Lifshits E, Mahmood S, Gainor JF, Affolter T, Lappin PB, Jain RK, Johnson TW, Shaw AT, Fantin VR, Smeal T, et al.
  • Journal Title: Cancer Cell Volume: 28 Issue: 1 Pages: 70-81
  • DOI: 10.1016/j.ccell.2015.05.010
  • Peer Reviewed / Int'l Joint Research
• [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
• [Journal Article] RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer. (2015)
  • Author(s): Niederst MJ, Sequist LV, Poirier JT, Mermel CH, Lockerman EL, Garcia AR, Katayama R, Costa C, Ross KN, Moran T, Howe E, Fulton LE, Mulvey HE, Bernardo LA, Mohamoud F, Miyoshi N, VanderLaan PA, Costa DB, Jänne PA, Borger DR, Ramaswamy S, Shioda T, Iafrate AJ, Getz G, Rudin CM, Mino-Kenudson M, Engelman JA.
  • Journal Title: Nature Communications Volume: 11 Issue: 1 Pages: 6377-6377
  • DOI: 10.1038/ncomms7377
  • Peer Reviewed / Open Access
• [Journal Article] Cabozantinib overcomes crizotinib resistance in ROS1 fusion-positive cancer. (2015)
  • Author(s): Katayama R, Kobayashi Y, Friboulet L, Lockerman EL, Koike S, Shaw AT, Engelman JA, Fujita N.
  • Journal Title: Clinical Cancer Research Volume: 21 Issue: 1 Pages: 166-174
  • DOI: 10.1158/1078-0432.ccr-14-1385
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Patient-derived models of acquired resistance can identify effective drug combinations for cancer. (2014)
  • Author(s): Crystal AS, Shaw AT, Sequist LV, Friboulet L, Niederst MJ, Lockerman EL, Frias RL, Gainor JF, Amzallag A, Greninger P, Lee D, Kalsy A, Gomez-Caraballo M, Elamine L, Howe E, Hur W, Lifshits E, Robinson HE, Katayama R, Faber AC, Awad MM, Ramaswamy S, Mino-Kenudson M, Iafrate AJ, Benes CH, Engelman JA.
  • Journal Title: Science Volume: 346 Issue: 6216 Pages: 1480-1486
  • DOI: 10.1126/science.1254721
  • Peer Reviewed
• [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] 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] 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
• [Presentation] Resistance mechanisms to tyrosine kinase inhibitors in fusion gene positive non-small cell lung cancer (2016)
  • Author(s): 片山量平
  • Organizer: Tenth AACR-JCA Joint Conference on Breakthroughs in Cancer Research: From Biology to Therapeutics
  • Place of Presentation: 米国、マウイ
  • Year and Date: 2016-02-14
  • Int'l Joint Research / Invited
• [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（Molecular mechanisms of ALK tyrosine kinase inhibitor resistance.） (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): Ryohei 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] Therapeutic strategies and resistance mechanisms in NTRK1 rearranged cancer (2015)
  • Author(s): 布施 美保 ジェーン、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: 2015-10-08
• [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: 2015-10-08
• [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
• [Presentation] Resistance mechanisms to ALK inhibitors (2015)
  • Author(s): Ryohei Katayama, Noriko Yanagitani, Sumie Koike, Takuya Sakashita, Satoru Kitazono, Makoto Nishio, Yasushi Okuno, Jeffrey A. Engelman, Alice T. Shaw, Naoya Fujita
  • Organizer: 第106回 アメリカ癌学会学術総会
  • Place of Presentation: 米国、フィラデルフィア
  • Year and Date: 2015-04-18
  • Int'l Joint Research
• [Presentation] New mechanisms of acquired resistance to ALK inhibitors (2014)
  • Author(s): 片山 量平
  • Organizer: 19th Japanese Foundation for Cancer Research-International Symposium on Cancer Chemotherapy (JFCR-ISCC)
  • Place of Presentation: 東京
  • Year and Date: 2014-12-10 – 2014-12-11
  • 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回日本癌学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
  • Invited
• [Presentation] ALK陽性肺がんにおけるAlectinib獲得耐性機構の同定 (2014)
  • Author(s): 小池 清恵，片山 量平，藤田直也
  • Organizer: 第73回日本癌学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] ROS1融合遺伝子陽性肺がんにおけるクリゾチニブ耐性機構とその克服法 (2014)
  • Author(s): 小林 由佳，片山 量平，藤田直也
  • Organizer: 第73回日本癌学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] ALK融合遺伝子陽性肺がんにおける新規Ceritinib耐性機構の同定 (2014)
  • Author(s): 坂下 卓也，片山 量平，藤田直也
  • Organizer: 第73回日本癌学会学術集会
  • Place of Presentation: 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回日本癌学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Resistance Mechanisms to ALK-TKIs (2014)
  • Author(s): 片山 量平
  • Organizer: 第12回日本臨床腫瘍学会学術集会
  • Place of Presentation: 福岡
  • Year and Date: 2014-07-17 – 2014-07-19
  • Invited
• [Presentation] Therapeutic strategies to overcome the crizotinib resistance in ROS1-rearranged lung cancers (2014)
  • Author(s): Ryohai Katayama, Yuka Kobayashi, Sumie Koike, Naoya Fujita
  • Organizer: 第104回 アメリカ癌学会学術総会（AACR Annual Meeting 2014)
  • Place of Presentation: サンディエゴ、米国
  • Year and Date: 2014-04-06 – 2014-04-09
• [Presentation] Targeting ALK or ROS1 Positive NSCLC: Mechanisms of and Strategies to Overcome Resistance (2014)
  • Author(s): Ryohei Katayama
  • Organizer: The 29th Nagoya International Cancer Treatment Symposium
  • Place of Presentation: 名古屋
  • Invited
• [Presentation] Clinical activity of the ALK inhibitor LDK378 in advanced, ALK-positive NSCLC (2013)
  • Author(s): Alice T. Shaw, Ranee Mehra, Dong-Wan Kim, Enriqueta Felip, Laura Q. M. Chow, D. Ross Camidge, Daniel S. W. Tan, Johan Vansteenkiste, Sunil Sharma, Tommaso De Pas, Juergen Wolf, Ryohei Katayama, Yvonne Lau, Meredith Goldwasser, Anthony L. Boral, Jeffrey A. Engelman
  • Organizer: 2013 ASCO Annual Meeting
  • Place of Presentation: 米国、シカゴ
• [Presentation] Therapeutic strategies to overcome crizotinib-resistance in NSCLC harboring ALK fusion (2013)
  • Author(s): 片山 量平
  • Organizer: 第11回日本臨床腫瘍学会学術集会
  • Place of Presentation: 仙台
  • Invited
• [Presentation] Cytotoxic 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回日本癌学会学術集会
  • Place of Presentation: 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回日本癌学会学術集会
  • Place of Presentation: 横浜
• [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
• [Remarks] ALKキナーゼ・ROS1キナーゼ融合遺伝子陽性肺がんの治療薬耐性化機構と克服薬の発見
  • URL: http://www.jfcr.or.jp/chemotherapy/pickup/index.html
• [Patent(Industrial Property Rights)] ＲＥＴ阻害薬耐性癌に対する治療剤 (2014)
  • Inventor(s): 矢野聖二、竹内伸司、藤田直也、片山量平
  • Industrial Property Rights Holder: 矢野聖二、竹内伸司、藤田直也、片山量平
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-10-31