High efficacy of erlotinib in Taiwanese NSCLC patients in an expanded access program study previously treated with chemotherapy

Perng, Reury Perng; Yang, James Chih‐Hsin; Chen, Yuh Min; Chang, Gee Chen; Lin, Meng C.; Hsieh, Ruey Kuen; Chu, Nei Min; Lai, Ruay-Sheng; Su, Wu Chou; Tsao, Chao Jung; Hsia, Te Chun; Chen, Hao Cheng; Chen, Chih‐Hung; Huang, Ming Shyan; Wang, Jui Long; Ho, Ming Lin; Chung, Chen-Yen; Yu, Chong Jen; Chang, W.C.; Kuo, Han Pin; Yu, Chih Teng; Lin, Zhong; Kao, Woei Yau

doi:10.1016/j.lungcan.2008.02.023

Cited by 26 publications

(29 citation statements)

References 21 publications

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“…In a randomized study conducted by the National Cancer Institute of Canada (BR.21) in secondand third-line NSCLC treatment, erlotinib significantly prolonged overall survival and decreased symptoms compared with placebo in patients with stage IIIB or stage IV NSCLC (7). These similar results are also seen in Taiwanese patients with proved stage IIIB/IV NSCLC who had received at least one line of standard chemotherapy or radiotherapy (35). Sensitivity to erlotinib has been associated with EGFR mutations, most commonly deletions of four to six amino acids in exon 19 or a point mutation (L858R) in exon 21.…”

Section: Discussionsupporting

confidence: 65%

Roles of MKK1/2-ERK1/2 and Phosphoinositide 3-Kinase–AKT Signaling Pathways in Erlotinib-Induced Rad51 Suppression and Cytotoxicity in Human Non–Small Cell Lung Cancer Cells

Ciou

Jhan

et al. 2009

Molecular Cancer Research

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Erlotinib (Tarceva) is a selective epidermal growth factor receptor tyrosine kinase inhibitor in the treatment of human non-small cell lung cancer (NSCLC). In this study, we investigated the roles of ERK1/2 and AKT signaling pathways in regulating Rad51 expression and cytotoxic effects in different NSCLC cell lines treated with erlotinib. Erlotinib decreased cellular levels of phosphorylated ERK1/2, phosphorylated AKT, Rad51 protein, and mRNA in erlotinib-sensitive H1650, A549, and H1869 cells, leading to cell death via apoptosis, but these results were not seen in erlotinib-resistant H520 and H1703 cells. Erlotinib decreased Rad51 protein levels by enhancing Rad51 mRNA and protein instability. Enforced expression of constitutively active MKK1 or AKT vectors could restore Rad51 protein levels, which were inhibited by erlotinib, and decrease erlotinib-induced cytotoxicity. Knocking down endogenous Rad51 expression by si-Rad51 RNA transfection significantly enhanced erlotinib-induced cytotoxicity. In contrast, overexpression of Rad51 by transfection with Rad51 vector could protect the cells from cytotoxic effects induced by erlotinib. Blocking the activations of ERK1/2 and AKT by MKK1/2 inhibitor (U0126) and phosphoinositide 3-kinase inhibitor (wortmannin) suppressed the expression of Rad51 and enhanced the erlotinib-induced cell death in erlotinib-resistant cells. In conclusion, suppression of Rad51 may be a novel therapeutic modality in overcoming drug resistance of erlotinib in NSCLC. (Mol Cancer Res 2009;7(8):1378-89)

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Section: Discussionsupporting

confidence: 65%

Roles of MKK1/2-ERK1/2 and Phosphoinositide 3-Kinase–AKT Signaling Pathways in Erlotinib-Induced Rad51 Suppression and Cytotoxicity in Human Non–Small Cell Lung Cancer Cells

Ciou

Jhan

et al. 2009

Molecular Cancer Research

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“…In this pathway, activating mutations of EGFR gene can lead to ligand-independent activation of the receptor, resulting in overactivation of downstream effectors. Based on these findings, EGFR inhibitors were developed and used for treatment of some cancers especially non-small cell lung cancer (NSCLC) (3). KRAS, a member of RAS family, plays an important role as a 'molecular switch' in the EGFR-RAS-RAF-MAP-kinase pathway.…”

Section: Introductionmentioning

confidence: 99%

Mutation detection of KRAS by high-resolution melting analysis in Chinese with gastric cancer

Liu

Liu²,

Li³

et al. 2009

Oncol Rep

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Abstract. KRAS proteins play an important role in regulating cell functions. A series of studies has revealed that mutations of KRAS are involved in gastric carcinogenesis. However, mutation status of KRAS remains unclear in gastric cancer from Chinese Mainland. It has been proved that KRAS mutation associates with resistance to epidermal growth factor receptor (EGFR) inhibitors. In this study, KRAS mutations were detected in 52 gastric adenocarcinomas from Northern China. High-resolution melting analysis (HRMA) was used and positive samples were confirmed by direct sequencing. Of the 52 cancers, KRAS mutations were found in 5 (9.6%). All cancers with KRAS mutation were from male patients. Frequencies of KRAS mutation were 14.3% (3/21) and 6.5% (2/31) in differentiated and undifferentiated cancers; 25% (1/4) and 8.3% (4/48) in early and advanced wall penetration cancers; and were 13.3% (2/15) and 8.1% (3/37) in without and with lymph node metastasis cancers, respectively. There was no significant correlation between KRAS mutation and clinicopathological features. There were 3 mutation types in the 5 mutations, including 2 G12D, 1 G12V and 2 G13D mutations. All codon 12 mutations were found in patients with lymph node metastasis and at advanced stage, whereas all codon 13 mutations were found in patients without lymph node metastasis and at early stage. These results support KRAS mutation may only be involved in carcinogenesis of partial gastric cancers and the different mutation types of KRAS may take part in development of gastric cancer at different stages. The resistance of partial gastric cancer patients to EGFR inhibitors may be induced by KRAS mutation.

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“…In a prospective cohort of chemotherapy-treated NSCLC patients in Taiwan Erlotinib Expanded Access Program (n=299), age ≥65 was a predictor of low response rate in multivariate analysis (response rate 20.4% in patient of age ≥65% vs. 34.4% in patients of age <65, p=0.0115). However, the disease control rates of two groups were similar (disease control rate 72.6% in patient of age ≥65% vs. 73.1% in patients of age <65, p=0.9185) [28]. Several phase II trials have been conducted in elderly patients in order to evaluate the role of single-agent EGFR TKI as the first-line therapy in this subset of patients ( Table 2).…”

Section: Clinical Studies Of Egfr-tki In Elderly Patientsmentioning

confidence: 99%

Epidermal growth factor receptor tyrosine kinase inhibitors in elderly or poor performance status patients with advanced non-small cell lung cancer

Lin

Yang

2009

Targ Oncol

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Elderly and poor performance status advanced non-small cell lung cancer (NSCLC) patients often tolerate chemotherapy poorly. Special approaches are needed for these patient populations. Tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR), erlotinib and gefitinib, are active agents in the treatment of advanced NSCLC. Several phase II trials have been conducted utilizing EGFR TKIs in elderly or poor performance status patients with advanced NSCLC. This review will summarize the results of erlotinib or gefitinib in these subsets of patients with advanced NSCLC.

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High efficacy of erlotinib in Taiwanese NSCLC patients in an expanded access program study previously treated with chemotherapy

Cited by 26 publications

References 21 publications

Roles of MKK1/2-ERK1/2 and Phosphoinositide 3-Kinase–AKT Signaling Pathways in Erlotinib-Induced Rad51 Suppression and Cytotoxicity in Human Non–Small Cell Lung Cancer Cells

Roles of MKK1/2-ERK1/2 and Phosphoinositide 3-Kinase–AKT Signaling Pathways in Erlotinib-Induced Rad51 Suppression and Cytotoxicity in Human Non–Small Cell Lung Cancer Cells

Mutation detection of KRAS by high-resolution melting analysis in Chinese with gastric cancer

Epidermal growth factor receptor tyrosine kinase inhibitors in elderly or poor performance status patients with advanced non-small cell lung cancer

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