| Project/Area Number |
18K15963
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 53030:Respiratory medicine-related
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| Research Institution | Hyogo Medical University |
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Principal Investigator |
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| Project Period (FY) |
2018-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | EGFR遺伝子変異陽性肺癌 / EGFRチロシンキナーゼ阻害薬 / β3インテグリン / YAP/TAZ / 癌幹細胞化 / EGFR-TKI耐性 / 肺癌 / integrin β3 / 癌幹細胞 / Hippo pathway / ITGB3 / 非小細胞肺癌 / EGFR遺伝子変異 |
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| Outline of Final Research Achievements |
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) bring about high response rate and survival benefit to patients with EGFR mutation-positive non-small cell lung cancer. However, they eventually develop acquired resistance and tumor regrows.
In the present study, we found that stimulation by EGFR-TKIs enhanced the expression of intergrin β3 (ITGB3) in EGFR mutation-positive lung cancer cells, which promoted nuclear translocation of YAP/TAZ thorough activation of YES. YAP/TAZ work as transcriptional co-activators and induce expression of target genes associated with cell cycle progression and anti-apoptosis. Therefore, we considered that lung cancer cells acquire resistance to EGFR-TKI through ITGB3-mediated YAP/TAZ activation. Collectively, ITGB3-YAP/TAZ signal is regarded as a novel therapeutic candidate to overcome EGFR-TKI resistance in patients with EGFR mutation-positive lung cancer.
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| Academic Significance and Societal Importance of the Research Achievements |
EGFR-TKIがEGFR遺伝子変異陽性肺癌症例に対し極めて有効で、生存期間の改善に貢献している事は数々のevidenceから明らかであるが、耐性化が必発である。耐性機序の解明についての研究も盛んに行われ、T790Mといったgate keeper遺伝子変異による機序、Metの増幅などによる代替シグナルの活性化、小細胞肺癌化など複数の機序が明らかとなっているが、依然として20%以上の耐性機序は未解明のままである。今回の実験で、YAP/TAZがEGFR-TKIの耐性機序に関わっている事が示された事は、EGFR-TKI耐性機序の克服のための新たな知見として重要であると考える。
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