Identification of molecular mechanisms other than genetic abnormalities in EGFR-TKI resistance of lung adenocarcinomas
| Project/Area Number |
24590440
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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 |
Human pathology
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| Research Institution | Sapporo Medical University (2014)
Jichi Medical University (2013)
地方独立行政法人神奈川県立病院機構神奈川県立がんセンター(臨床研究所) (2012) |
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Principal Investigator |
SAKUMA Yuji 札幌医科大学, 医学部, 准教授 (10364514)
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| Project Period (FY) |
2012-04-01 – 2015-03-31
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| Project Status |
Completed (Fiscal Year 2014)
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| Budget Amount *help |
¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2012: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Keywords | 肺腺癌 / EGFR遺伝子変異 / 薬剤抵抗性 / 上皮間葉転換 / アポトーシス抵抗性 / autophagy / 細胞外基質 |
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| Outline of Final Research Achievements |
Lung cancers harboring EGFR mutations depend on constitutive activation of the kinase for survival. We have identified two new molecular mechanisms that play a role in the EGFR-mutant cells’ resistance to EGFR inhibitors. (1) EGFR-mutant cells in 3D culture resist EGFR inhibition compared with suspended cells. Degradation of IκB and activation of NF-κB are observed only in 3D-cultured cells. Inhibiting NF-κB enhances the efficacy of the EGFR TKIs in 3D-cultured cells. (2) Two EGFR-mutated lung adenocarcinoma cell lines, HCC827 and HCC4006, contain a subpopulation of cells that have undergone epithelial-to-mesenchymal transition and survive independent of activated EGFR. These EGFR-independent cancer cells, herein termed gefitinib-resistant (GR) cells, demonstrate higher levels of basal autophagy than their parental cells. Depletion of the essential autophagy gene, ATG5, by siRNA markedly reduces GR cell viability, suggesting that GR cells can survive with constant autophagic flux.
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Report
(4 results)
Research Products
(7 results)
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[Journal Article] Enhanced autophagy is required for survival in EGFR-independent EGFR-mutant lung adenocarcinoma cells.2013
Author(s)
Sakuma Y, Matsukuma S, Nakamura Y, Yoshihara M, Koizume S, Sekiguchi H, Saito H, Nakayama H, Kameda Y, Yokose T, Oguni S, Niki T, and Miyagi Y.
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Journal Title
Lab Invest.
Volume: 93
Issue: 10
Pages: 1137-1146
DOI
Related Report
Peer Reviewed
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