8 results on '"Lai, Chun-Liang"'
Search Results
2. Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Treatment Response in Advanced Lung Adenocarcinomas with G719X/L861Q/S768I Mutations.
- Author
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Chiu CH, Yang CT, Shih JY, Huang MS, Su WC, Lai RS, Wang CC, Hsiao SH, Lin YC, Ho CL, Hsia TC, Wu MF, Lai CL, Lee KY, Lin CB, Yu-Wung Yeh D, Chuang CY, Chang FK, Tsai CM, Perng RP, and Chih-Hsin Yang J
- Subjects
- Adenocarcinoma genetics, Adult, Aged, Aged, 80 and over, Disease-Free Survival, ErbB Receptors antagonists & inhibitors, Female, Gefitinib, Humans, Lung Neoplasms genetics, Male, Middle Aged, Survival Rate, Treatment Outcome, Adenocarcinoma drug therapy, ErbB Receptors genetics, Erlotinib Hydrochloride therapeutic use, Lung Neoplasms drug therapy, Mutation, Protein Kinase Inhibitors therapeutic use, Quinazolines therapeutic use
- Abstract
Background: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is the standard therapy for advanced lung adenocarcinomas with common EGFR mutations. Preclinical studies have suggested that uncommon G719X, L861Q, and S768I mutations are also sensitive to EGFR-TKIs. However, the efficacy of EGFR-TKIs in patients with these uncommon mutations remains unclear., Methods: A nationwide survey was performed to collect data from gefitinib and erlotinib treatment outcomes of patients with stage IIIB/IV lung adenocarcinoma bearing EGFR G719X/L861Q/S768I mutations. The results were compared with those regarding patients with exon 19 deletions or L858R mutations., Results: One hundred and sixty-one patients with uncommon EGFR mutations were enrolled from 18 institutes throughout Taiwan. Mutations of G719X, L861Q, S768I, G719X + L861Q, and G719X + S768I were observed in 78, 57, 7, 9, and 10 patients, respectively. After receiving EGFR-TKI treatment, patients with uncommon mutations exhibited a significantly inferior tumor response rate (41.6% vs. 66.5%; p < 0.001) and progression-free survival (median, 7.7 vs. 11.4 months; p < 0.001) than patients with common mutations. Among the patients who used EGFR-TKIs as first-line treatment, there was a significant difference in overall survival between these two groups of patients (median, 24.0 vs. 29.7 months; p = 0.005)., Conclusion: Gefitinib and erlotinib are active in patients with G719X/L861Q/S768I mutations; however, less effective than in those with common mutations.
- Published
- 2015
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3. Molecular mechanism of membrane binding of the GRP1 PH domain.
- Author
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Lai CL, Srivastava A, Pilling C, Chase AR, Falke JJ, and Voth GA
- Subjects
- Blood Proteins chemistry, Blood Proteins metabolism, Cell Membrane metabolism, Kinetics, Membrane Proteins chemistry, Membrane Proteins metabolism, Models, Molecular, Molecular Dynamics Simulation, Phosphatidylinositol Phosphates chemistry, Phosphatidylinositol Phosphates metabolism, Phosphatidylserines chemistry, Phosphatidylserines metabolism, Phospholipids chemistry, Phospholipids metabolism, Phosphoproteins chemistry, Phosphoproteins metabolism, Protein Binding, Protein Structure, Tertiary, Static Electricity, Lipid Bilayers chemistry, Lipid Bilayers metabolism, Receptors, Cytoplasmic and Nuclear chemistry, Receptors, Cytoplasmic and Nuclear metabolism
- Abstract
The pleckstrin homology (PH) domain of the general receptor of phosphoinositides 1 (GRP1) protein selectively binds to a rare signaling phospholipid, phosphatidylinositol (3,4,5)-trisphosphate (PIP3), in the membrane. The specific PIP3 lipid docking of GRP1 PH domain is essential to protein cellular function and is believed to occur in a stepwise process, electrostatic-driven membrane association followed by the specific PIP3 binding. By a combination of all-atom molecular dynamics (MD) simulations, coarse-grained analysis, electron paramagnetic resonance (EPR) membrane docking geometry, and fluorescence resonance energy transfer (FRET) kinetic studies, we have investigated the search and bind process in the GRP1 PH domain at the molecular scale. We simulated the two membrane binding states of the GRP1 PH domain in the PIP3 search process, before and after the GRP1 PH domain docks with the PIP3 lipid. Our results suggest that the background anionic phosphatidylserine lipids, which constitute around one-fifth of the membrane by composition, play a critical role in the initial stages of recruiting protein to the membrane surface through non-specific electrostatic interactions. Our data also reveal a previously unseen transient membrane association mechanism that is proposed to enable a two-dimensional "hopping" search of the membrane surface for the rare PIP3 target lipid. We further modeled the PIP3-bound membrane-protein system using the EPR membrane docking structure for the MD simulations, quantitatively validating the EPR membrane docking structure and augmenting our understanding of the binding interface with atomic-level detail. Several observations and hypotheses reached from our MD simulations are also supported by experimental kinetic studies., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
- Full Text
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4. Membrane binding and self-association of the epsin N-terminal homology domain.
- Author
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Lai CL, Jao CC, Lyman E, Gallop JL, Peter BJ, McMahon HT, Langen R, and Voth GA
- Subjects
- Adaptor Proteins, Vesicular Transport chemistry, Cell Membrane metabolism, Electron Spin Resonance Spectroscopy, Models, Molecular, Molecular Dynamics Simulation, Protein Binding, Adaptor Proteins, Vesicular Transport metabolism, Protein Structure, Tertiary
- Abstract
Epsin possesses a conserved epsin N-terminal homology (ENTH) domain that acts as a phosphatidylinositol 4,5-bisphosphate-lipid-targeting and membrane-curvature-generating element. Upon binding phosphatidylinositol 4,5-bisphosphate, the N-terminal helix (H(0)) of the ENTH domain becomes structured and aids in the aggregation of ENTH domains, which results in extensive membrane remodeling. In this article, atomistic and coarse-grained (CG) molecular dynamics (MD) simulations are used to investigate the structure and the stability of ENTH domain aggregates on lipid bilayers. EPR experiments are also reported for systems composed of different ENTH-bound membrane morphologies, including membrane vesicles as well as preformed membrane tubules. The EPR data are used to help develop a molecular model of ENTH domain aggregates on preformed lipid tubules that are then studied by CG MD simulation. The combined computational and experimental approach suggests that ENTH domains exist predominantly as monomers on vesiculated structures, while ENTH domains self-associate into dimeric structures and even higher-order oligomers on the membrane tubes. The results emphasize that the arrangement of ENTH domain aggregates depends strongly on whether the local membrane curvature is isotropic or anisotropic. The molecular mechanism of ENTH-domain-induced membrane vesiculation and tubulation and the implications of the epsin's role in clathrin-mediated endocytosis resulting from the interplay between ENTH domain membrane binding and ENTH domain self-association are also discussed., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
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5. Gefitinib enhances cytotoxicities of antimicrotubule agents in non-small-cell lung cancer cells exhibiting no sensitizing epidermal growth factor receptor mutation.
- Author
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Tsai CM, Chiu CH, Chang KT, Chen JT, Lai CL, Chen YM, and Hsiao SY
- Subjects
- Antineoplastic Agents pharmacology, Antineoplastic Combined Chemotherapy Protocols, Apoptosis drug effects, Blotting, Western, Carcinoma, Non-Small-Cell Lung pathology, Cell Line, Tumor, Drug Resistance, Multiple, Drug Resistance, Neoplasm, Drug Synergism, Gefitinib, Genes, MDR genetics, Humans, Lung Neoplasms pathology, Paclitaxel pharmacology, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Carcinoma, Non-Small-Cell Lung drug therapy, ErbB Receptors genetics, Lung Neoplasms drug therapy, Microtubules drug effects, Mutation genetics, Quinazolines pharmacology, Tubulin Modulators pharmacology
- Abstract
Introductions: Although randomized clinical trials showed no benefit from combining epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) with standard chemotherapy for advanced non-small-cell lung cancer (NSCLC), better results might be obtained by combining EGFR-TKI with individual agents that are substrates for the adenosine triphosphate binding cassette transporters (ABCTs) because EGFR-TKIs can inhibit their efflux. The combination effects deserved to be further examined in vitro., Methods: The combination effects of gefitinib with three antimicrotubule agents (AMTAs), paclitaxel, docetaxel or vinorelbine, or with gemcitabine were tested in 17 NSCLC cell lines using the tetrazolium colorimetric assay and classical isobole method. The effects of drug combinations, identified by the values of mean combination index (mCIs), were correlated with the expression levels of ABCTs. Dose-versus-log-response curves were analyzed to further evaluate the possible mechanisms of drug interactions., Results: Synergistic gefitinib/AMTA interactions were observed in the tested cell lines. The synergism was more robust in the four lines overexpressing de novo or acquired P-glycoprotein (Pgp; individual mCIs range, 0.484-0.859; all p values were < 0.05), or in 12 cell lines exhibiting no sensitizing EGFR mutations (group mCIs for gefitinib/paclitaxel, gefitinib/docetaxel, and gefitinib/vinorelbine were 0.869, 0.82, and 0.853, respectively. All p values were < 0.02). The synergism could be observed in cells expressing nearly undetectable Pgp and other ABCTs tested in this study. The combination of gefitinib/gemcitabine was additive (mCI = 1.027)., Conclusions: Combined gefitinib/AMTAs showed synergism in NSCLC cells harboring no sensitizing EGFR mutations. Gefitinib could enhance AMTA effects through mechanisms not restricted to Pgp blockage.
- Published
- 2012
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6. Antagonism between gefitinib and cisplatin in non-small cell lung cancer cells: why randomized trials failed?
- Author
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Tsai CM, Chen JT, Stewart DJ, Chiu CH, Lai CL, Hsiao SY, Chen YM, and Chang KT
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- Adenocarcinoma drug therapy, Adenocarcinoma genetics, Adenocarcinoma, Bronchiolo-Alveolar drug therapy, Adenocarcinoma, Bronchiolo-Alveolar genetics, Carcinoma, Large Cell drug therapy, Carcinoma, Large Cell genetics, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Squamous Cell drug therapy, Carcinoma, Squamous Cell genetics, Cisplatin administration & dosage, Drug Resistance, Neoplasm genetics, ErbB Receptors genetics, Gefitinib, Genes, ras, Humans, Lung Neoplasms genetics, Mutation genetics, Paclitaxel administration & dosage, Quinazolines administration & dosage, Randomized Controlled Trials as Topic, Treatment Failure, Tumor Cells, Cultured, Antineoplastic Combined Chemotherapy Protocols pharmacology, Carcinoma, Non-Small-Cell Lung drug therapy, Clinical Trials, Phase III as Topic standards, Lung Neoplasms drug therapy
- Abstract
Introduction: Four phase III randomized trials adding epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors to standard chemotherapeutics in patients with advanced non-small cell lung cancer (NSCLC) have failed to show benefits. The mechanism of these failures was examined., Methods: Fifteen previously untreated NSCLC cell lines were simultaneously treated with gefitinib plus cisplatin. Three exhibited sensitizing-EGFR mutations. Three selected lines were further tested with paclitaxel/cisplatin, paclitaxel/gefitinib, and paclitaxel/cisplatin/gefitinib combinations. The tetrazolium colorimetric assay with application of the classic isobole method was used, and dose-versus-log-response curves (DRCs) were analyzed to evaluate possible resistance mechanisms., Results: Of the 15 cell lines tested, combined gefitinib/cisplatin was significantly antagonistic in 10 wild-type and three sensitizing-EGFR mutant cell lines (group mean combination index = 1.184, 95% confidence interval = 1.12-1.24, p = 0.001). The mean combination index values of paclitaxel/cisplatin/gefitinib were higher than or comparable with those of paclitaxel/cisplatin and paclitaxel/gefitinib. DRC analysis consistently showed nonsaturable passive resistance, suggesting that gefitinib at 0.001 to 0.3 μM can interfere with cisplatin cell entry (at concentrations >1-3 μM) in a dose-dependent manner and lead to antagonism. This antagonism may or may not be schedule dependent in different cell lines., Conclusions: In most EGFR wild-type or sensitizing-mutant NSCLC cells, the concomitant gefitinib/cisplatin combination showed antagonism, likely because gefitinib interfered with cisplatin entry into the cell. The findings that three-drug combination was not better than the two-drug combinations are in accordance with the results of the randomized trials. The EGFR-tyrosine kinase inhibitor/platinum antagonism is a possible reason for the failure of those randomized trials.
- Published
- 2011
- Full Text
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7. Different efficacies of erlotinib and gefitinib in taiwanese patients with advanced non-small cell lung cancer: a retrospective multicenter study.
- Author
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Fan WC, Yu CJ, Tsai CM, Huang MS, Lai CL, Hsia TC, Tien YJ, Huang SF, Wu CH, Chou KT, Lee YC, Perng RP, and Chen YM
- Subjects
- Adenocarcinoma drug therapy, Adenocarcinoma pathology, Aged, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Squamous Cell drug therapy, Carcinoma, Squamous Cell pathology, Erlotinib Hydrochloride, Female, Gefitinib, Humans, Lung Neoplasms pathology, Male, Neoplasm Staging, Prognosis, Quinazolines administration & dosage, Retrospective Studies, Survival Rate, Taiwan, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy
- Abstract
Introduction: Epidermal growth factor receptor-tyrosine kinase inhibitors are used as effective first-line and salvage therapy in the treatment of advanced non-small cell lung cancer (NSCLC) patients in East Asia. The objective of this study was to compare the efficacy of gefitinib and erlotinib in Taiwanese patients with advanced NSCLC., Methods: Clinical data of NSCLC patients treated with gefitinib or erlotinib from January 2004 to December 2008 were collected retrospectively. Five tertiary referral centers in Taiwan participated in the study., Results: Of the 1122 patients enrolled, 506 (45%) were female, 594 (53%) were never smokers or former light smokers, and 867 (77%) were diagnosed with adenocarcinoma. Epidermal growth factor receptor-tyrosine kinase inhibitors were prescribed as first-line treatment in 465 (41%) patients and as second-line or salvage therapy in 657 patients (59%). The objective response rate was similar between the gefitinib and erlotinib treatment groups, while disease control rate was 58.9 and 65.8% (p = 0.025), respectively. Median progression-free survival of gefitinib and erlotinib groups was 3.6 and 4.6 months, respectively (p = 0.027). Median overall survival of gefitinib and erlotinib groups was 9.6 and 10.7 months, respectively (p = 0.013)., Conclusion: Taiwanese patients with advanced NSCLC treated with erlotinib reported higher disease control rate, longer progression-free survival, and overall survival compared with patients treated with gefitinib.
- Published
- 2011
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8. Membrane docking geometry and target lipid stoichiometry of membrane-bound PKCα C2 domain: a combined molecular dynamics and experimental study.
- Author
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Lai CL, Landgraf KE, Voth GA, and Falke JJ
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- Calcium metabolism, Cations, Divalent metabolism, Electron Spin Resonance Spectroscopy, Models, Chemical, Models, Molecular, Molecular Dynamics Simulation, Protein Binding, Membrane Lipids metabolism, Membrane Proteins metabolism, Phosphatidylinositol 4,5-Diphosphate metabolism, Phosphatidylserines metabolism, Protein Kinase C-alpha metabolism
- Abstract
Protein kinase Cα (PKCα) possesses a conserved C2 domain (PKCα C2 domain) that acts as a Ca(2+)-regulated membrane targeting element. Upon activation by Ca(2+), the PKCα C2 domain directs the kinase protein to the plasma membrane, thereby stimulating an array of cellular pathways. At sufficiently high Ca(2+) concentrations, binding of the C2 domain to the target lipid phosphatidylserine (PS) is sufficient to drive membrane association; however, at typical physiological Ca(2+) concentrations, binding to both PS and phosphoinositidyl-4,5-bisphosphate (PIP(2)) is required for specific plasma membrane targeting. Recent EPR studies have revealed the membrane docking geometries of the PKCα C2 domain docked to (i) PS alone and (ii) both PS and PIP(2) simultaneously. These two EPR docking geometries exhibit significantly different tilt angles relative to the plane of the membrane, presumably induced by the large size of the PIP(2) headgroup. The present study utilizes the two EPR docking geometries as starting points for molecular dynamics simulations that investigate atomic features of the protein-membrane interaction. The simulations yield approximately the same PIP(2)-triggered change in tilt angle observed by EPR. Moreover, the simulations predict a PIP(2):C2 stoichiometry approaching 2:1 at a high PIP(2) mole density. Direct binding measurements titrating the C2 domain with PIP(2) in lipid bilayers yield a 1:1 stoichiometry at moderate mole densities and a saturating 2:1 stoichiometry at high PIP(2) mole densities. Thus, the experiment confirms the target lipid stoichiometry predicted by EPR-guided molecular dynamics simulations. Potential biological implications of the observed docking geometries and PIP(2) stoichiometries are discussed., (Copyright © 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2010
- Full Text
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