| Project/Area Number |
19K23930
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| Research Category |
Grant-in-Aid for Research Activity Start-up
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| Allocation Type | Multi-year Fund |
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| Review Section |
0901:Oncology and related fields
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| Research Institution | Okayama University (2020, 2022-2023)
National Cancer Center Japan (2019) |
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Principal Investigator |
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| Project Period (FY) |
2019-08-30 – 2024-03-31
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| Project Status |
Completed (Fiscal Year 2023)
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| Budget Amount *help |
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | EGFR肺癌 / β-catenin / Drug-tolerant persisters / EGFR遺伝子変異 / β-catenin経路 / Drug-tolerant cells / EGFR肺がん / オシメルチニブ / EGFR遺伝子変異陽性肺癌 |
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| Outline of Research at the Start |
EGFR遺伝子に活性型変異を有する肺腺癌において、EGFR-TKIに対する耐性克服は臨床的に重要な課題である。第一世代、第二世代のEGFR-TKI耐性機構としての二次変異T790M、第三世代EGFR-TKIの耐性機構としてのMet増幅、C797Sが明らかにされ、それらに対する治療法の開発が進められている。これらはgeneticな耐性獲得後の確立された新たなシグナル系に対する分子標的治療の開発であるが、これまでの臨床試験の結果を鑑みるに、さらなる薬剤耐性を生じ、根本的な治療となり得ない。本研究では薬剤耐性獲得前のDTPsが如何に形成されるかを明らかにし、新たな治療法創出を目的としている。
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| Outline of Final Research Achievements |
β-catenin, one of the key players in Wnt signalling, is known to play an important role in tumour development in colorectal cancer, etc. However, its role in lung cancer remains unclear. Our previous studies have shown that β-catenin is essential for lung tumourigenesis by active EGFR and that β-catenin binds directly to active EGFR and is tyrosine-phosphorylated.We found that the YAP-TBX5 pathway, which is different from the classical pathway, showed increased activity in the presence of active EGFR. The Src-family pathway is also activated in the presence of active EGFR, suggesting that phosphorylation of β-catenin-Y333 tyrosine residues by the Src family may cause a molecular switch from the classical pathway to the YAP-TBX5 pathway. βcatenin-YAP-TBX5 pathway regulates anti-apoptosis-related genes such as the BcL2L1 gene, and suppression of these pathways may be a new therapeutic target in addition to the strategy of suppressing EGFR activity with EGFR-TKI.
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| Academic Significance and Societal Importance of the Research Achievements |
活性型EGFR遺伝子変異陽性肺癌において、Drug-tolerant persisters(DTPs)形成の詳細なメカニズムの一端を明らかにし、DTPs形成阻害による、耐性克服の新たな治療方法創出が可能であることを示した。
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