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Small Molecule T315 Promotes Casitas B-Lineage Lymphoma-Dependent Degradation of Epidermal Growth Factor Receptor via Y1045 Autophosphorylation.

Small Molecule T315 Promotes Casitas B-Lineage Lymphoma-Dependent Degradation of Epidermal Growth Factor Receptor via Y1045 Autophosphorylation.

Authors :
Kuo-Yen Huang
Shih-Han Kao
Wen-Lung Wang
Chi-Yuan Chen
Tzu-Hung Hsiao
Salunke, Santosh B.
Chen, Jeremy J. W.
Kang-Yi Su
Shuenn-Chen Yang
Tse-Ming Hong
Ching-Shih Chen
Pan-Chyr Yang
Huang, Kuo-Yen
Kao, Shih-Han
Wang, Wen-Lung
Chen, Chi-Yuan
Hsiao, Tzu-Hung
Su, Kang-Yi
Yang, Shuenn-Chen
Hong, Tse-Ming
Source :
American Journal of Respiratory & Critical Care Medicine; 4/1/2016, Vol. 193 Issue 7, p753-766, 14p, 2 Diagrams, 5 Graphs
Publication Year :
2016

Abstract

<bold>Rationale: </bold>Despite the fact that tyrosine kinase inhibitors (TKIs) have been found effective in treating patients harboring activating mutations of epidermal growth factor receptor (EGFR), an acquired secondary mutation, T790M, which lowers the affinity to TKIs, can lead to EGFR TKI resistance after this standard treatment.<bold>Objectives: </bold>To evaluate the effect of small molecule T315 on EGFR degradation and its therapeutic efficacy in vitro and in vivo.<bold>Methods: </bold>Lung adenocarcinoma cells were treated with T315, and cell proliferation and apoptotic proportion were determined by the CellTiter 96 AQueous MTS (3-[4,5-dimethylthiazol-2-yl]-5-[3-carboxymethoxyphenyl]-2-[4-sulfophenyl]-2H-tetrazolium, inner salt) assay and flow cytometry. The effects of T315 on EGFR mRNA and protein levels, autophosphorylation, ubiquitination, and degradation were evaluated by real-time polymerase chain reaction and Western blot, respectively. Direct targeting of T315 to EGFR was confirmed by the in vitro kinase assay and mass spectrometry. Finally, the preclinical effect of T315 was validated in the murine xenograft model in combination with a second-generation TKI, afatinib.<bold>Measurements and Main Results: </bold>We identified T315 as a novel, potent small molecule for suppressing cancer cell proliferation in vitro and in vivo. The therapeutic effect was verified after T315 was combined with a second-generation TKI, afatinib, compared with a single drug administration. We found a new mechanism of action, in that T315 appears to directly bind EGFR and triggers EGFR-Y1045 autophosphorylation, whereby its degradation is triggered through the ubiquitin-proteasome pathway.<bold>Conclusions: </bold>Our evidence suggests that T315 is a novel class of anticancer drug that is able to inhibit the growth of EGFR-TKI-resistant lung adenocarcinoma cells by inducing the degradation of EGFR. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
1073449X
Volume :
193
Issue :
7
Database :
Complementary Index
Journal :
American Journal of Respiratory & Critical Care Medicine
Publication Type :
Academic Journal
Accession number :
114262032
Full Text :
https://doi.org/10.1164/rccm.201502-0250OC