Dataset Information

Contribution of EGFR and ErbB-3 Heterodimerization to the EGFR Mutation-Induced Gefitinib- and Erlotinib-Resistance in Non-Small-Cell Lung Carcinoma Treatments.

ABSTRACT: EGFR mutation-induced drug resistance has become a major threat to the treatment of non-small-cell lung carcinoma. Essentially, the resistance mechanism involves modifications of the intracellular signaling pathways. In our work, we separately investigated the EGFR and ErbB-3 heterodimerization, regarded as the origin of intracellular signaling pathways. On one hand, we combined the molecular interaction in EGFR heterodimerization with that between the EGFR tyrosine kinase and its inhibitor. For 168 clinical subjects, we characterized their corresponding EGFR mutations using molecular interactions, with three potential dimerization partners (ErbB-2, IGF-1R and c-Met) of EGFR and two of its small molecule inhibitors (gefitinib and erlotinib). Based on molecular dynamics simulations and structural analysis, we modeled these mutant-partner or mutant-inhibitor interactions using binding free energy and its components. As a consequence, the mutant-partner interactions are amplified for mutants L858R and L858R_T790M, compared to the wild type EGFR. Mutant delL747_P753insS represents the largest difference between the mutant-IGF-1R interaction and the mutant-inhibitor interaction, which explains the shorter progression-free survival of an inhibitor to this mutant type. Besides, feature sets including different energy components were constructed, and efficient regression trees were applied to map these features to the progression-free survival of an inhibitor. On the other hand, we comparably examined the interactions between ErbB-3 and its partners (EGFR mutants, IGF-1R, ErbB-2 and c-Met). Compared to others, c-Met shows a remarkably-strong binding with ErbB-3, implying its significant role in regulating ErbB-3 signaling. Moreover, EGFR mutants corresponding to poor clinical outcomes, such as L858R_T790M, possess lower binding affinities with ErbB-3 than c-Met does. This may promote the communication between ErbB-3 and c-Met in these cancer cells. The analysis verified the important contribution of IGF-1R or c-Met in the drug resistance mechanism developed in lung cancer treatments, which may bring many benefits to specialized therapy design and innovative drug discovery.

SUBMITTER: Wang DD

PROVIDER: S-EPMC4439022 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Contribution of EGFR and ErbB-3 Heterodimerization to the EGFR Mutation-Induced Gefitinib- and Erlotinib-Resistance in Non-Small-Cell Lung Carcinoma Treatments.

Wang Debby D DD Ma Lichun L Wong Maria P MP Lee Victor H F VH Yan Hong H

PloS one 20150520 5

EGFR mutation-induced drug resistance has become a major threat to the treatment of non-small-cell lung carcinoma. Essentially, the resistance mechanism involves modifications of the intracellular signaling pathways. In our work, we separately investigated the EGFR and ErbB-3 heterodimerization, regarded as the origin of intracellular signaling pathways. On one hand, we combined the molecular interaction in EGFR heterodimerization with that between the EGFR tyrosine kinase and its inhibitor. For ...[more]

PMID: 25993617

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Project description:BackgroundSeveral EGFR-tyrosine kinase inhibitors (EGFR-TKIs) including erlotinib, gefitinib, afatinib and icotinib are currently available as treatment for patients with advanced non-small-cell lung cancer (NSCLC) who harbor EGFR mutations. However, no head to head trials between these TKIs in mutated populations have been reported, which provides room for indirect and integrated comparisons.MethodsWe searched electronic databases for eligible literatures. Pooled data on objective response rate (ORR), progression free survival (PFS), overall survival (OS) were calculated. Appropriate networks for different outcomes were established to incorporate all evidences. Multiple-treatments comparisons (MTCs) based on Bayesian network integrated the efficacy and specific toxicities of all included treatments.ResultsTwelve phase III RCTs that investigated EGFR-TKIs involving 1821 participants with EGFR mutation were included. For mutant patients, the weighted pooled ORR and 1-year PFS of EGFR-TKIs were significant superior to that of standard chemotherapy (ORR: 66.6% vs. 30.9%, OR 5.46, 95%CI 3.59 to 8.30, P<0.00001; 1-year PFS: 42.9% vs. 9.7%, OR 7.83, 95%CI 4.50 to 13.61; P<0.00001) through direct meta-analysis. In the network meta-analyses, no statistically significant differences in efficacy were found between these four TKIs with respect to all outcome measures. Trend analyses of rank probabilities revealed that the cumulative probabilities of being the most efficacious treatments were (ORR, 1-year PFS, 1-year OS, 2-year OS): erlotinib (51%, 38%, 14%, 19%), gefitinib (1%, 6%, 5%, 16%), afatinib (29%, 27%, 30%, 27%) and icotinib (19%, 29%, NA, NA), respectively. However, afatinib and erlotinib showed significant severer rash and diarrhea compared with gefitinib and icotinib.ConclusionsThe current study indicated that erlotinib, gefitinib, afatinib and icotinib shared equivalent efficacy but presented different efficacy-toxicity pattern for EGFR-mutated patients. Erlotinib and afatinib revealed potentially better efficacy but significant higher toxicities compared with gefitinib and icotinib.

Project description:BackgroundSeveral randomized controlled trials have suggested that adjuvant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) were associated with prolonged disease-free survival (DFS) in EGFR-mutated NSCLC patients after radical resection, comparing with chemotherapy or placebo. We aimed to compare the effectiveness of different first-generation EGFR-TKIs as adjuvant treatment in real-world setting.MethodsEarly-stage EGFR mutated NSCLC patients who underwent radical resection and treated with first-generation EGFR-TKIs (gefitinib, erlotinib, icotinib) as adjuvant therapy between Feb 2010 and Jan 2019 were retrieved from a prospectively-maintained database in our center. The primary endpoint was DFS in stage II/III (TNM 8th) patients with exploratory endpoint regarding DFS in stage I patients. Sensitivity analyses were based on propensity score matched (PSM) cohorts. Treatment failure patterns among different TKIs were also compared.ResultsOf 588 eligible patients, 198 patients (33.7%) received gefitinib, 106 patients (17.9%) received erlotinib, and 284 patients (48.2%) received icotinib. The median DFS of stage II/III patients in the gefitinib, erlotinib and icotinib group were 36.1 months (95% CI, 23.9-49.4), 42.8 months (95% CI, 29.6-97.8), and 32.5 months (95% CI, 23.9-49.4), respectively, with no significant difference (log-rank test P=0.22). There was also no significant difference in DFS among stage I patients receiving different TKIs (P=0.12). PSM adjustments and multivariate analyses adjusting for other confounders revealed similar results. In addition, there were no significant differences in treatment failure pattens in different EGFR-TKI arms, especially in terms of brain metastases (6.1% in gefitinb, 7.5% in erlotinib, 3.9% in icotinib) and bone metastases (8.6% in gefitinb, 9.4% in erlotinib, 7.0% in icotinib).ConclusionsThis first and largest real-world study showed that gefitinib, erlotinib, and icotinib demonstrated comparable clinical effectiveness as adjuvant therapy for patients with early-stage EGFR mutated NSCLC.

Dataset Information

Contribution of EGFR and ErbB-3 Heterodimerization to the EGFR Mutation-Induced Gefitinib- and Erlotinib-Resistance in Non-Small-Cell Lung Carcinoma Treatments.

Publications

Contribution of EGFR and ErbB-3 Heterodimerization to the EGFR Mutation-Induced Gefitinib- and Erlotinib-Resistance in Non-Small-Cell Lung Carcinoma Treatments.

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