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Drug resistance mechanisms and therapeutic strategies in rare driver oncogene positive cancers

Research Project

Project/Area Number 16H04715
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Tumor therapeutics
Research InstitutionJapanese 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, 部長 (60435542)

Research Collaborator SETO yosuke  
UCHIBORI ken  
NISHIO makoto  
YANAGITANI noriko  
TAKEUCHI kengo  
OH-HARA tomoko  
KOIKE sumie  
OKADA koutaroh  
SHIMIZU yuki  
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000)
Fiscal Year 2018: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2017: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2016: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000)
KeywordsDriver Oncogene / 獲得耐性 / 耐性克服法 / 耐性 / 肺がん / ALK / ROS1 / EGFR / チロシンキナーゼ阻害薬(TKI) / 融合遺伝子 / 分子標的薬 / 耐性機構 / 耐性克服療法 / チロシンキナーゼ阻害薬 / ERBB2
Outline of Final Research Achievements

In lung cancer, low frequency driver oncogenes such as ALK, ROS1, RET and NTRK fusion genes are targeted by the development of multiple tyrosine kinase inhibitors. These TKIs often shows marked tumor shrinkage for a couple years, however, the tumor inevitably relapses due to the emergence of acquired resistance. In the final year, we found and reported that 14 compound mutations in ALK kinase domain confers the resistance to most potent 3rd generation ALK inhibitor lorlatinib, but some of these resistance mutations became re-sensitive to 1st or 2nd generation ALK-TKIs. In addition, in ROS1 rearranged lung cancer, a couple of patient derived cell lines were newly established from the malignant pleural effusion, and evaluated a new inhibitor under collaboration. In addition, we clarified and published the relationship between the order of EGFR-TKIs use and the pattern of resistance mutation emergence.

Academic Significance and Societal Importance of the Research Achievements

低頻度ながらDriver Oncogene陽性肺がんに対しては高い腫瘍縮小効果を示す治療薬が、複数開発され臨床応用されてきたが、獲得耐性が大きな問題として立ちはだかる。本研究において、複数の新規耐性機構と克服法を明らかにしてきたが、中でも重複耐性変異による第3世代阻害薬耐性が再び第1,2世代阻害薬への感受性を取り戻すという発見は、今後の治療順番を考えたり、耐性時にそのメカニズムに合わせた最適な治療法選択の重要性を提起するインパクトの大きな発見といえる。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • Research Products

    (50 results)

All 2019 2018 2017 2016 Other

All Int'l Joint Research (2 results) Journal Article (14 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 14 results,  Open Access: 11 results,  Acknowledgement Compliant: 2 results) Presentation (30 results) (of which Int'l Joint Research: 5 results,  Invited: 16 results) Remarks (3 results) Patent(Industrial Property Rights) (1 results)

  • [Int'l Joint Research] MGH Cancer Center(米国)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] Gustave Roussy Cancer Campus(フランス)

    • Related Report
      2018 Annual Research Report
  • [Journal Article] Secreted PD-L1 variants mediate resistance to PD-L1 blockade therapy in non-small cell lung cancer2019

    • Author(s)
      Gong Bo, Kiyotani Kazuma, Sakata Seiji, Nagano Seiji, Kumehara Shun, Baba Satoko, Besse Benjamin, Yanagitani Noriko, Friboulet Luc, Nishio Makoto, Takeuchi Kengo, Kawamoto Hiroshi, Fujita Naoya, Katayama Ryohei
    • Journal Title

      The Journal of Experimental Medicine

      Volume: 216 Issue: 4 Pages: 982-1000

    • DOI

      10.1084/jem.20180870

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Epithelial-to-Mesenchymal Transition Is a Mechanism of ALK Inhibitor Resistance in Lung Cancer Independent of ALK Mutation Status.2019

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

      Cancer Res

      Volume: 79(7) Issue: 7 Pages: 1658-1670

    • DOI

      10.1158/0008-5472.can-18-2052

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Prediction of ALK mutations mediating ALK-TKIs resistance and drug re-purposing to overcome the resistance2019

    • Author(s)
      Okada Koutaroh、Araki Mitsugu、Sakashita Takuya、Ma Biao、Kanada Ryo、Yanagitani Noriko、Horiike Atsushi、Koike Sumie、Oh-hara Tomoko、Watanabe Kana、Tamai Keiichi、Maemondo Makoto、Nishio Makoto、Ishikawa Takeshi、Okuno Yasushi、Fujita Naoya、Katayama Ryohei
    • Journal Title

      EBioMedicine

      Volume: 41 Pages: 105-119

    • DOI

      10.1016/j.ebiom.2019.01.019

    • NAID

      120006892063

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Recurrent 8q24 rearrangement in blastic plasmacytoid dendritic cell neoplasm: association with immunoblastoid cytomorphology, MYC expression, and drug response.2018

    • Author(s)
      Kana Sakamoto, Ryohei Katayama, Reimi Asaka, Seiji Sakata, Satoko Baba, Hideki Nakasone, Sumie Koike, Naoko Tsuyama, Akito Dobashi, Makoto Sasaki, Ryo Ichinohasama, Emi Takakuwa, Rie Yamazaki, Jun Takizawa, Takahiro Maeda, Miwako Narita, Koji Izutsu, Yoshinobu Kanda, Koichi Ohshima and Kengo Takeuchi
    • Journal Title

      Leukemia

      Volume: 32 Issue: 12 Pages: 2590-2603

    • DOI

      10.1038/s41375-018-0154-5

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 3D culture system containing gellan gum restores oncogene dependence in ROS1 rearrangements non-small cell lung cancer.2018

    • Author(s)
      Bo Gong, Tomoko Oh-hara, Naoya Fujita, Ryohei Katayama
    • Journal Title

      Biochem. Biophys. Res. Commun.

      Volume: 501 Issue: 2 Pages: 527-533

    • DOI

      10.1016/j.bbrc.2018.05.031

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification of mutation accumulation as resistance mechanism emerging in first-line osimertinib treatment.2018

    • Author(s)
      Ken Uchibori, Naohiko Inase, Makoto Nishio, Naoya Fujita, Ryohei Katayama
    • Journal Title

      J. Thorac. Oncol.

      Volume: 13 Issue: 7 Pages: 915-925

    • DOI

      10.1016/j.jtho.2018.04.005

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] High ratio of T790M to EGFR activating mutations correlate with the osimertinib response in non-small-cell lung cancer2018

    • Author(s)
      Ariyasu Ryo、Nishikawa Shingo、Uchibori Ken、Oh-hara Tomoko、Yoshizawa Takahiro、Dotsu Yosuke、Koyama Junji、Saiki Masafumi、Sonoda Tomoaki、Kitazono Satoru、Yanagitani Noriko、Horiike Atsushi、Inase Naohiko、Kasahara Kazuo、Nishio Makoto、Katayama Ryohei
    • Journal Title

      Lung Cancer

      Volume: 117 Pages: 1-6

    • DOI

      10.1016/j.lungcan.2017.12.018

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Drug resistance in anaplastic lymphoma kinase-rearranged lung cancer2018

    • Author(s)
      Katayama Ryohei
    • Journal Title

      Cancer Science

      Volume: 109 Issue: 3 Pages: 572-580

    • DOI

      10.1111/cas.13504

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] TKI-addicted ROS1-rearranged cells are destined to survival or death by the intensity of ROS1 kinase activity2017

    • Author(s)
      Hayato Ogura, Yuka Nagatake-Kobayashi, Jun Adachi, Takeshi Tomonaga, Naoya Fujita, Ryohei Katayama
    • Journal Title

      Sci. Rep.

      Volume: 7 Issue: 1 Pages: 5519-5519

    • DOI

      10.1038/s41598-017-05736-9

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 8. Mechanisms of resistance to NTRK inhibitors and therapeutic strategies in NTRK1-rearranged cancers.2017

    • Author(s)
      Miho Jane Fuse, Koutaroh Okada, Tomoko Oh-hara, Hayato Ogura, Naoya Fujita, Ryohei Katayama
    • Journal Title

      Mol Cancer Ther.

      Volume: 16 Issue: 10 Pages: 2130-2143

    • DOI

      10.1158/1535-7163.mct-16-0909

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [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

    • Related Report
      2017 Annual Research Report 2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [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

    • Related Report
      2016 Annual Research Report
    • 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

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / 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

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] Cellular diversity by genetic and non-genetic alteration in cancer induces acquired resistance in NSCLC.2019

    • Author(s)
      Ryohei Katayama, Bo Gong, Koutaroh Okada, Makoto Nishio, and Naoya Fujita
    • Organizer
      11th AACR-JCA Joint Conference on Breakthroughs in Cancer Research: Biology to Precision Medicine
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Drug repurposing: overcoming the acquired resistance with other target inhibitors2018

    • Author(s)
      Ryohei Katayama, Koutaroh Okada, Bo Gong, Ken Uchibori, Makoto Nishio, and Naoya Fujita
    • Organizer
      The 23th Taiwan Joint Cancer Conference 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] ALK陽性肺がん獲得耐性から考えるキナーゼ進化2018

    • Author(s)
      片山 量平
    • Organizer
      第41回日本呼吸器内視鏡学会学術集会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 肺がん分子標的薬耐性メカニズムの探索と耐性機構予測への挑戦2018

    • Author(s)
      片山 量平、岡田 康太郎、藤田 直也
    • Organizer
      第22回 日本がん分子標的治療学会学術総会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 次世代ALK阻害薬Lorlatinib耐性重複変異の発見とその治療戦略の示唆2018

    • Author(s)
      岡田 康太郎、藤田 直也、片山 量平
    • Organizer
      第22回 日本がん分子標的治療学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Drug repurposing: overcoming the acquired resistance with other target inhibitors2018

    • Author(s)
      Ryohei Katayama, Bo Gong, Koutaroh Okada, Ken Uchibori, Makoto Nishio, and Naoya Fujita
    • Organizer
      6th JCA-AACR Joint Conference
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 非接着培養を用いた新規ROS1阻害剤評価系の構築2018

    • Author(s)
      キョウ 博、大原 智子、小池 清恵、藤田 直也、片山 量平
    • Organizer
      第22回 日本がん分子標的治療学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Prediction of TKI resistance in lung cancer through the experimental models and in silico simulations2018

    • Author(s)
      片山 量平、藤田 直也
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] BRAF V600E変異陽性大腸がんにおける新たなサブグループの発見2018

    • Author(s)
      清水 裕貴、キョウ 博、大原 智子、長山 聡、藤田 直也、片山 量平
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] KRAS変異大腸がんにおける分子プロファイリングに基づく新規併用治療法の探索2018

    • Author(s)
      キョウ 博、清水 裕貴、大原 智子、長山 聡、藤田 直也、片山 量平
    • Organizer
      第77回 日本癌学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 三次元培養システムによるRET再構成肺癌細胞の薬物感受性評価システムの確立2018

    • Author(s)
      小池 清恵、藤田 直也、片山 量平
    • Organizer
      第77回 日本癌学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Her2活性化変異陽性肺がん細胞株の樹立とキナーゼ阻害薬の評価2018

    • Author(s)
      大原 智子、藤田 直也、片山 量平
    • Organizer
      第77回 日本癌学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Anticancer drug resistance caused by cancer cell evolution and diversity2018

    • Author(s)
      片山 量平、藤田 直也
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Detection, prediction, and investigation of the resistance mechanisms to EGFR-TKIs in EGFR mutated NSCLC2018

    • Author(s)
      片山 量平
    • Organizer
      第59回 日本肺癌学会学術集会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [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
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] 10.Driver oncogene陽性肺がんにおける多様な分子標的薬耐性とその克服法2017

    • Author(s)
      片山量平、藤田直也
    • Organizer
      第20回日本がん分子標的治療学会学術集会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 11.Drug Repurposing: Overcoming drug resistance mutation with tyrosine kinase inhibitor for different target2017

    • Author(s)
      片山量平、藤田直也
    • Organizer
      第15回日本臨床腫瘍学会学術集会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 12.Driver Oncogene陽性肺がんにおける獲得耐性の分子基盤と新たな治療戦略2017

    • Author(s)
      片山量平
    • Organizer
      第75回日本癌学会学術総会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 13.Molecular Basis of TKI resistant cells in driver oncogene positive NSCLC2017

    • Author(s)
      片山量平
    • Organizer
      第58回日本肺癌学会学術集会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] Identification of the molecular mechanisms of resistance to NTRK inhibitors and the potential therapeutic strategies in NTRK1-rearranged cancers2017

    • Author(s)
      Ryohei Katayama, Miho Jane Fuse, Tomoko Oh-hara, Hayato Ogura, Naoya Fujita
    • Organizer
      AACR annual meeting
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Analysis of “drug addiction” mechanisms in the drug-resistant ROS1-rearranged cancer cells2017

    • Author(s)
      Hayato Ogura, Jun Adachi, Takeshi Tomonaga, Naoya Fujita, Ryohei Katayama
    • Organizer
      AACR annual meeting
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] G1202R変異型EML4-ALKの変異蓄積による次世代ALK阻害剤Lorlatinib耐性の獲得2017

    • Author(s)
      岡田康太郎、藤田直也、片山量平
    • Organizer
      第20回日本がん分子標的治療学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] cMET増幅を介したALK阻害薬耐性とその克服法2017

    • Author(s)
      小池清恵、藤田直也、片山量平
    • Organizer
      第20回日本がん分子標的治療学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] NTRK融合遺伝子陽性がんにおける獲得耐性機構2017

    • Author(s)
      大原智子、佐藤重男、藤田直也、片山量平
    • Organizer
      第75回日本癌学会学術総会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Overcoming the C797S/T790M mutation mediated Osimertinib resistance by Brigatinib combined with anti-EGFR antibody2017

    • Author(s)
      内堀健、藤田直也、片山量平
    • Organizer
      第75回日本癌学会学術総会
    • Related Report
      2017 Annual Research Report
  • [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
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] Tumor cell and stromal cell mediated drug resistance in driver oncogene positive non-small cell lung cancer2016

    • 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
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] TKI-resistance mechanisms in ALK or ROS1 rearranged non-small cell lung cancer.2016

    • Author(s)
      片山 量平
    • Organizer
      第14回日本臨床腫瘍学会学術集会
    • Place of Presentation
      兵庫県神戸市
    • Year and Date
      2016-07-28
    • Related Report
      2016 Annual Research Report
    • 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)
      片山量平、小池清恵、大原智子、西尾誠人、藤田直也
    • 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
    • Related Report
      2016 Annual Research Report
  • [Presentation] ABCトランスポーターを介したALK阻害薬耐性2016

    • Author(s)
      小池清恵、藤田直也、片山量平
    • 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
    • Related Report
      2016 Annual Research Report
  • [Remarks] ALK融合遺伝子陽性肺がんに対する薬剤耐性変異予測と、 既存薬を活用した耐性克服法の発見

    • URL

      https://www.jfcr.or.jp/laboratory/news/5935.html

    • Related Report
      2018 Annual Research Report
  • [Remarks] 分泌型PD-L1バリアントを介した免疫チェックポイント阻害薬耐性機序の発見

    • URL

      https://www.jfcr.or.jp/laboratory/news/6432.html

    • Related Report
      2018 Annual Research Report
  • [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

    • Related Report
      2016 Annual Research Report
  • [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
    • Related Report
      2016 Annual Research Report

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Published: 2016-04-21   Modified: 2020-03-30  

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