Development of target therapy against KRAS mutant lung cancer stratified by EMT status.
| Project/Area Number |
16K07164
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Tumor therapeutics
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| Research Institution | Aichi Cancer Center Research Institute (2017-2018)
Kanazawa University (2016) |
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Principal Investigator |
EBI Hiromichi 愛知県がんセンター(研究所), がん標的治療TR分野, 分野長 (00645145)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | KRAS / EMT / feedback / MEK / SHP2 / FGFR1 / 肺がん / 上皮間葉移行 / 腫瘍不均一性 / フィードバック / 癌 / シグナル伝達 / トランスレーショナルリサーチ |
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| Outline of Final Research Achievements |
Whereas the mitogen-activated protein kinase (MAPK) is a well-known effector pathway of KRAS, blocking this pathway with clinically-available MAPK inhibitors is relatively ineffective. We identified that epithelial-to-mesenchymal transition (EMT) rewires the expression of receptor tyrosine kinases, leading to differential feedback activation of the MAPK pathway following MEK inhibition. In epithelial-like KRAS mutant lung cancers, this feedback was attributed to ERBB3. In contrast, in mesenchymal-like KRAS mutant lung cancers, FGFR1 was dominantly expressed but suppressed by the negative regulator sprouty proteins; MEK inhibition led to de-repression of SPRY4 and subsequent FGFR1-mediated re-activation of MEK. Therapeutically, the combination of MEK inhibitor and FGFR inhibitor induced cell death in vitro and tumor regressions in vivo. We established the rationale and a therapeutic approach to treat KRAS mutant lung cancers effectively.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究課題を通し、KRAS変異肺がんが上皮間葉移行状態により2種類に分類されることを初めて示した。さらに、それぞれのKRAS変異肺がんに優位に発現している受容体をMEKとともに阻害することにより、KRAS変異肺がんを治療できる可能性を示した。MEK阻害薬単剤では治療効果が不十分であることがこれまでの臨床試験の結果明らかとなっており、本研究は今後の臨床開発の方向性を示すとともに、KRAS変異肺がんに対し個別化医療を行える可能性を示している。本研究の成果は米国癌学会雑誌（Cancer Discovery）に掲載された。
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Report
(4 results)
Research Products
(31 results)
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[Journal Article] ADAM17 selectively activates the IL‐6 trans‐signaling/ERK MAPK axis in KRAS‐addicted lung cancer2019
Author(s)
Saad MI, Alhayyani S, McLeod L, Liang Yu L, Alanazi M, Deswaerte V, Tang K, Jarde T, Smith JA, Prodanovic Z, Tate MD, Balic JJ, Watkins DM, Cain JE, Bozinovski S, Algar E, Kohmoto T, Ebi H, Ferlin W, Garbers C, Ruwanpura S, Sagi I, Rose-John S, Jenkins BJ
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Journal Title
EMBO Molecular Medicine
Volume: 11
Issue: 4
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Increased Synthesis of MCL-1 Protein Underlies Initial Survival of EGFR-Mutant Lung Cancer to EGFR Inhibitors and Provides a Novel Drug Target2018
Author(s)
Song KA, Hosono Y, Turner C, Jacob S, Lochmann TL, Murakami Y, Patel NU, Ham J, Hu B, Powell KM, Coon CM, Windle B, Oya Y, Koblinski JE, Harada H, Leverson JD, Souers AJ, Hata AN, Boikos SA, Yatabe Y, Ebi H, Faber AC
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Journal Title
Clinical Cancer Research
Volume: 24
Issue: 22
Pages: 5658-5672
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Recurrence of renal cell carcinoma diagnosed using contralateral adrenal biopsy with endoscopic ultrasound-guided fine-needle aspiration.2016
Author(s)
Tanimoto A, Takeuchi S, Yaegashi H, Kotani H, Kitai H, Nanjo S, Ebi H, Yamashita K, Mouri H, Ohtsubo K, Ikeda H, Yano S
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Journal Title
Mol Clin Oncol.
Volume: 4
Pages: 537-540
Related Report
Peer Reviewed
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