| 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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| 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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