Response to Erlotinib in First-Line Treatment of Non–Small-Cell Lung Cancer in a White Male Smoker with Squamous-Cell Histology

Achille, Michaela; Gallegos-Ruiz, M. I.; Giaccone, Giuseppe; Soria, Jean‐Charles

doi:10.3816/clc.2006.n.050

Cited by 11 publications

(10 citation statements)

References 6 publications

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“…Three of 12 patients (25%, 95% CI 9-43%) with lung SCC achieved PR. Furthermore, objective responses to erlotinib have been observed in patients with advanced NSCLC who do not possess active EGFR mutations [8,28]. As both EGFR-TKIs, erlotinib and gefitinib, had effects on lung SCC patients, there might be additional mechanisms other than activating EGFR mutations.…”

Section: Discussionmentioning

confidence: 98%

“…However, some lung SCC patients could derive a clinical benefit to the EGFR-TKIs in daily practice. In 2006, Achille et al reported a case of one white male former smoker with advanced lung SCC, who responded to erlotinib [8]. No one previous chemotherapy regimen, demonstrated female gender, adenocarcinoma, Asian ethnicity and non-smoking history as clinical predictors of better response [7].…”

Section: Introductionmentioning

confidence: 97%

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Retrospective study of erlotinib in patients with advanced squamous lung cancer

Tseng¹,

Yang²,

Chen³

et al. 2012

Lung Cancer

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 97%

Retrospective study of erlotinib in patients with advanced squamous lung cancer

Tseng¹,

Yang²,

Chen³

et al. 2012

Lung Cancer

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“…One recent report has shown that one White male former smoker with advanced-staged squamous cell lung cancer without EGFR tyrosine kinase mutations had a good response to first-line erlotinib (38).…”

Section: Discussionmentioning

confidence: 99%

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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“…Prospective studies with gefitinib or erlotinib in patients harboring EGFR-activating mutations reported response rates ranging from 60% to 82%, suggesting that these drugs might be a valuable alternative to chemotherapy in selected patients (9,10). However, in the BR.21 trial, the treatment with erlotinib resulted in statistically significant improvements in overall survival (OS) and quality of life in all of the subsets of patients (11,12), and several studies reported that patients without mutations responded to EGFR-TKIs (13,14). Similarly, some NSCLC cell lines with normal EGFR status are sensitive to these agents (15), suggesting that the question of who should receive EGFR-TKI therapy is still not completely answered and other molecular factors need to be identified.…”

Section: Introductionmentioning

confidence: 97%

Association of Polymorphisms inAKT1andEGFRwith Clinical Outcome and Toxicity in Non–Small Cell Lung Cancer Patients Treated with Gefitinib

Giovannetti

Zucali

Peters

et al. 2010

Molecular Cancer Therapeutics

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EGFR mutations are strongly predictive of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor activity in non-small cell lung cancer (NSCLC), but resistance mechanisms are not completely understood. The interindividual variability in toxicity also points out to the need of novel pharmacogenetic markers to select patients before therapy. Therefore, we evaluated the associations between EGFR and AKT1 polymorphisms and outcome/toxicity in gefitinib-treated NSCLC patients. Polymorphic loci in EGFR, and AKT1, and EGFR and K-Ras mutations were assessed in DNA isolated from blood samples and/or paraffin-embedded tumor from 96 gefitinib-treated NSCLC patients. Univariate and multivariate analyses compared genetic variants with clinical efficacy and toxicity using Fisher's, log-rank test, and Cox's proportional hazards model. AKT1-SNP4 association with survival was also evaluated in 127 chemotherapy-treated/gefitinib-naive patients, whereas its relationship with AKT1 expression and gefitinib cytotoxicity was studied in 15 NSCLC cell lines. AKT1-SNP4 A/A genotype was associated with shorter time-to-progression (P = 0.04) and overall survival (P = 0.007). Multivariate analyses and comparison with the gefitinib-nontreated population underlined its predictive significance, whereas the in vitro studies showed the association of lower AKT1 mRNA levels with gefitinib resistance. In contrast, EGFR-activating mutations were significantly correlated with response, longer time-to-progression, and overall survival, whereas EGFR −191C/A (P < 0.001), −216 G/T (P < 0.01), and R497K (P = 0.02) polymorphisms were strongly associated with grade >1 diarrhea. AKT1-SNP4 A/A genotype seems to be a candidate biomarker of primary resistance, whereas EGFR −191C/A, −216G/T, and R497K polymorphisms are associated with diarrhea when using gefitinib in NSCLC patients, thus offering potential new tools for treatment optimization.

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Response to Erlotinib in First-Line Treatment of Non–Small-Cell Lung Cancer in a White Male Smoker with Squamous-Cell Histology

Cited by 11 publications

References 6 publications

Retrospective study of erlotinib in patients with advanced squamous lung cancer

Retrospective study of erlotinib in patients with advanced squamous lung cancer

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

Association of Polymorphisms inAKT1andEGFRwith Clinical Outcome and Toxicity in Non–Small Cell Lung Cancer Patients Treated with Gefitinib

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