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학술연구/단체지원/교육 등 연구자 활동을 지속하도록 DBpia가 지원하고 있어요.
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- 학술저널
- 저자정보
- 발행연도
- 2013.1
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Lapatinib, a dual inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) tyrosine kinases, has shown promising results as a growth inhibitor of HER2-positive cancer cells in vitro. However, similar to other EGFR-targeting drugs, acquired resistance to lapatinib by HER2-positive cancer cells remains a major clinical challenge. To elucidate resistance mechanisms to EGFR/HER2-targeting agents, we performed a systematic quantitative comparison of the phosphoproteome of lapatinib-resistant (LR) human gastric cancer cells (SNU216-LR) versus parental cells (SNU216) using a titanium dioxide (TiO2) phosphopeptide enrichment method and analysis with a Q-Exactive hybrid quadrupole-Orbitrap mass spectrometer. Biological network analysis of differentially expressed phosphoproteins revealed apparent constitutive activation of the MET-axis phosphatidylinositide 3-kinase (PI3K)/a-serine/threonine-protein kinase (AKT) and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathways in SNU216-LR. Inhibition of the PI3K/AKT and MAPK/ERK signaling pathways in SNU216-LR also leads to cell cycle arrest, confirming the biological network analysis. Lapatinib sensitivity was restored when cells were treated with several molecular targeting agents in combination with lapatinib. Thus, by integrating phosphoproteomic data, protein networks and effects of signaling pathway modulation on cell proliferation, we found that SNU216-LR maintains constitutive activation of the PI3K/AKT and MAPK/ERK pathways in a MET-dependent manner. These findings suggest that pathway activation is a key compensatory intracellular phospho-signaling event that may govern gastric cancer cell resistance to drug treatment.
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참고문헌 (23)
참고문헌 신청
[학술지(정기간행물)]
Beausoleil SA / 2006 / A probability-based approach for high-throughput protein phosphorylation analysis and site localization / Nat Biotechnol 24 : 1285 ~ 1292
Cameron DA / 2008 / Drug insight: intracellular inhibitors of HER2? clinical development of lapatinib in breast cancer. Nature clinical practice / Oncology 5 : 512 ~ 520
Chen CT / 2012 / Met activation mediates resistance to lapatinib inhibition of HER2-amplified gastric cancer cells / Mol Cancer Ther 11 : 660 ~ 669
Chen FL / 2008 / Acquired resistance to small molecule ErbB2 tyrosine kinase inhibitors / Clin Cancer Res 14 : 6730 ~ 6734
Beausoleil SA / 2006 / A probability-based approach for high-throughput protein phosphorylation analysis and site localization / Nat Biotechnol 24 : 1285 ~ 1292
Cameron DA / 2008 / Drug insight: intracellular inhibitors of HER2? clinical development of lapatinib in breast cancer. Nature clinical practice / Oncology 5 : 512 ~ 520
Chen CT / 2012 / Met activation mediates resistance to lapatinib inhibition of HER2-amplified gastric cancer cells / Mol Cancer Ther 11 : 660 ~ 669
Chen FL / 2008 / Acquired resistance to small molecule ErbB2 tyrosine kinase inhibitors / Clin Cancer Res 14 : 6730 ~ 6734
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