2014 Fiscal Year Final Research Report
Combining Afatinib and Cetuximab synergistically increases their cytotoxicity for EGFR T790M-harboring cells
Project/Area Number |
24591184
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Research Field |
Respiratory organ internal medicine
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Research Institution | Miyagi Prefectural Hospital Organization Miyagi Cancer Center |
Principal Investigator |
MAEMODNO MAKOTO 地方独立行政法人宮城県立病院機構宮城県立がんセンター(研究所), がん先進治療開発研究部, 特任研究員 (40344676)
|
Co-Investigator(Kenkyū-buntansha) |
TANAKA Nobuyuki 地方独立法人宮城県立病院機構宮城県立がんセンター(研究所), がん先進治療開発研究部, 部長 (60280872)
|
Project Period (FY) |
2012-04-01 – 2015-03-31
|
Keywords | 癌 / 非小細胞肺癌 / 治療法 |
Outline of Final Research Achievements |
TKIs are effective for NSCLC patients with EGFR-activating mutations. However, these patients eventually develop resistance, most frequently by T790M mutation. Combining a second-generation TKI with an anti-EGFR monoclonal antibody has been shown to improve clinical outcomes, although the mechanism remains elusive. To investigate this mechanism, we used EGFR-negative K562 cells. Double-mutant EGFRs were moderately sensitive to afatinib, but minimally affected by cetuximab. Combining afatinib and cetuximab synergistically increased cytotoxity for K562 cells carrying double-mutant EGFRs. Apoptosis in these cells was preceded by induction of BIM and activation of Caspase-3 and PARP. Afatinib induced EGFR recycling to the cell surface, leading to the cetuximab-mediated recognition and subsequent degradation. These results suggest that the synergistic effect exerted by afatinib and cetuximab against NSCLCs has a potential in the future clinical application.
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Free Research Field |
呼吸器内科学
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