Identification of signaling pathway involving drug resistant in RET-rearranged lung cancer
Project/Area Number |
17K15036
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Research Category |
Grant-in-Aid for Young Scientists (B)
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Allocation Type | Multi-year Fund |
Research Field |
Tumor therapeutics
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Research Institution | National Cancer Center Japan |
Principal Investigator |
Nakaoku Takashi 国立研究開発法人国立がん研究センター, 研究所, 研究員 (20779491)
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Project Period (FY) |
2017-04-01 – 2019-03-31
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Project Status |
Completed (Fiscal Year 2018)
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Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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Keywords | RET / 非小細胞肺癌 / チロシンキナーゼ阻害剤 / 薬剤耐性 / NF-kB / 非小細胞肺がん / RET融合遺伝子 / 肺腺がん / 癌 / シグナル伝達 |
Outline of Final Research Achievements |
The purpose of this study was to clarify the drug resistance mechanism in RET fusion gene positive lung cancer against RET tyrosine kinase inhibitor, and to obtain knowledge to overcome the resistance. We identified secondary S904F mutation on the activation loop of RET kinase domain from the patient who got re-progression of the tumor after treatment of vandetanib. In silico molecular dynamic simulation analysis as well as in vitro assay using Ba/F3 cells and purified kinase protein revealed the S904F mutation causing drug resistance by destabilizing RET kinase domain protein and vandetanib complex by the allosteric effect (Nakaoku T, et al. Nat Commun. 2018).
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Academic Significance and Societal Importance of the Research Achievements |
本研究により、薬剤の結合部位から離れた位置に存在するアロステリック効果を持つ遺伝子変異が分子標的薬剤に対する耐性を獲得する原因となることが明らかになった。今回の研究に用いた手法は、がん細胞に起こる変異の機能を解明し、治療の方針決定の手助けになることが期待される。また、その薬剤耐性変異の克服を目指した研究を行っており、その成果はより効果的な非小細胞肺がんへの治療法の開発につながる可能性がある。
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Report
(3 results)
Research Products
(11 results)
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[Journal Article] A secondary RET mutation in the activation loop conferring resistance to vandetanib.2018
Author(s)
Nakaoku T, Kohno T, Araki M, Niho S, Chauhan R, Knowles PP, Tsuchihara K, Matsumoto S, Shimada Y, Mimaki S, Ishii G, Ichikawa H, Nagatoishi S, Tsumoto K, Okuno Y, Yoh K, McDonald NQ, Goto K
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Journal Title
Nature Communications
Volume: 9
Issue: 1
Pages: 625-625
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Presentation] A Secondary RET Mutation in the Activation Loop Conferring Resistance to Vandetanib Through Allosteric Effects2018
Author(s)
Takashi Nakaoku, Mitsugu Araki, Seiji Niho, Rakhee Chauhan, Phillip P. Knowles, Katsuya Tsuchihara, Shingo Matsumoto, Yoko Shimada, Sachiyo Mimaki, Genichiro Ishii, Hitoshi Ichikawa, Satoru Nagatoishi, Kouhei Tsumoto, Yasushi Okuno, Kiyotaka Yoh, Neil Q. McDonald, Koichi Goto, Takashi Kohno
Organizer
Cambridge Healthtech Institute's 2018 Drug Discovery Chemistry conference
Related Report
Int'l Joint Research
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[Presentation] A secondary RET mutation allosterically conferring resistance to vandetanib2018
Author(s)
Takashi Nakaoku, Takashi Kohno, Mitsugu Araki, Seiji Niho, Rakhee Chauhan, Phillip P. Knowles, Katsuya Tsuchihara, Shingo Matsumoto, Yoko Shimada, Sachiyo Mimaki, Genichiro Ishii, Hitoshi Ichikawa, Yasushi Okuno, Kiyotaka Yoh, Neil Q. McDonald, Koichi Goto
Organizer
AACR annual meeting 2018
Related Report
Int'l Joint Research
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[Presentation] Druggable oncogene fusions and resistance mechanisms in lung cancer2018
Author(s)
Takashi Nakaoku, Mitsugu Araki, Seiji Niho, Rakhee Chauhan, Phillip P. Knowles, Katsuya Tsuchihara6, Shingo Matsumoto, Yoko Shimada, Sachiyo Mimaki, Genichiro Ishii, Hitoshi Ichikawa, Yasushi Okuno, Kiyotaka Yoh, Neil Q. McDonald, Koichi Goto, Takashi Kohno
Organizer
The 6th JCA-AACR Special Joint Conference
Related Report
Int'l Joint Research / Invited
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