Prospective Study of Gefitinib in Epidermal Growth Factor Receptor Fluorescence In Situ Hybridization–Positive/Phospho-Akt–Positive or Never Smoker Patients With Advanced Non–Small-Cell Lung Cancer: The ONCOBELL Trial

Cappuzzo, Federico; Ligorio, Claudia; Jänne, Pasi A.; Toschi, Luca; Rossi, Elisa; Trisolini, Rocco; Paioli, Daniela; Holmes, Amie L.; Magrini, Elisabetta; Finocchiaro, Giovanna; Bartolini, Stefania; Cancellieri, Alessandra; Ciardiello, Fortunato; Patelli, Marco; Crinò, Lucio; Varella‐Garcia, Marileila

doi:10.1200/jco.2006.09.4300

Cited by 200 publications

(139 citation statements)

References 46 publications

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“…Das et al (22) showed that NSCLC cell lines harboring tyrosine kinase domain mutations exhibit marked sensitivity to irradiation, as a result of delayed DNA repair kinetics, defective radiation-induced arrest during DNA synthesis or mitosis, and pronounced increases in apoptosis or the occurrence of micronuclei. On the other hand, the ONCO-BELL study reported a poorer response rate in patients with increased EGFR copy number and p-AKT positivity, which indicate activated PI3K-AKT signaling (23).…”

Section: Discussionmentioning

confidence: 99%

Targeting Epidermal Growth Factor Receptor–Associated Signaling Pathways in Non–Small Cell Lung Cancer Cells: Implication in Radiation Response

Choi

Ryu

Kim

et al. 2010

Molecular Cancer Research

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Several studies have shown solid evidence for the potential value of targeting epidermal growth factor receptor (EGFR) signaling to enhance the antitumor activity of radiation. However, therapeutic resistance has emerged as an important clinical issue. Here, we investigated whether strategies for targeting EGFR-associated downstream signaling would radiosensitize a panel of non-small cell lung cancer cell lines. Inhibition of K-RAS using RNA interference attenuated downstream signaling and increased radiosensitivity of A549 and H460 cells, whereas inhibition of EGFR did not. A549 cells harboring a K-RAS mutation at codon V12 were radiosensitized by small interfering RNA (siRNA) targeting this codon. H460 cells having mutation at codon V61 was radiosensitized by siRNA targeting of this mutation. K-RAS siRNA did not radiosensitize H1299 cells possessing wild-type K-RAS. Inhibition of the phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin pathway led to significant radiosensitization of the two cell lines, whereas selective inhibition of extracellular signal-regulated kinase signaling did not. Inhibitors targeting the PI3K-AKT-mTOR pathway also abrogated G 2 arrest following irradiation and induced γH2AX foci formation. A dual inhibitor of class I PI3K and mammalian target of rapamycin effectively increased the radiosensitivity of A549 and H460 cells. Inhibition of PI3K-AKT signaling was associated with the downregulation of DNA-PKs. Although apoptosis was the primary mode of cell death when cells were pretreated with LY294002 or AKT inhibitor VIII, cells pretreated with rapamycin or PI-103 showed mixed modes of cell death, including apoptosis and autophagy. Our results suggest possible mechanisms for counteracting EGFR prosurvival signaling implicated in radioresistance and offer an alternative strategy for overcoming resistance to EGFR inhibitors used in combination with irradiation.

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Section: Discussionmentioning

confidence: 99%

Targeting Epidermal Growth Factor Receptor–Associated Signaling Pathways in Non–Small Cell Lung Cancer Cells: Implication in Radiation Response

Choi

Ryu

Kim

et al. 2010

Molecular Cancer Research

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“…However, the ability of these markers to consistently predict clinical response is controversial (Zhu et al, 2008). Although some clinical trials have failed to find an association between response to gefitinib and expression of EGFR, several studies have shown that increased EGFR gene copy number, as determined by FISH, and EGFR protein overexpression correlated with improved response and overall survival (OS) (Hirsch et al, 2005;Cappuzzo et al, 2005aCappuzzo et al, , 2007Sequist et al, 2007). Furthermore, increased HER2 gene copy number was also found to predict response to EGFR TKIs in EGFR-positive patients with NSCLC (Cappuzzo et al, 2005a;Soh et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Predictive value of EGFR and HER2 overexpression in advanced non-small-cell lung cancer

2009

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Epidermal growth factor receptor (EGFR) and HER2 are cell surface receptor tyrosine kinases (TKs) that transduce growth signals through dimerization with HER family receptors. The heterodimerization of EGFR with HER2 induces a more potent activation of EGFR TK than does EGFR homodimerization. When tumor cells overexpress both EGFR and HER2, they exhibit aggressive tumor cell growth, owing to the increased potential for EGFR/HER2 heterodimerization and signaling. Gefitinib and erlotinib are EGFR TK inhibitors (EGFR TKIs) and have antitumor activity in 8-18% of patients with advanced non-small-cell lung cancer (NSCLC). Certain patient subsets are particularly responsive to EGFR TKIs. Analyses of biomarkers from patients in clinical studies of EGFR TKIs show correlations between objective tumor response and EGFR overexpression, as detected by immunohistochemistry and increased gene copy number measured by fluorescence in situ hybridization analysis. Furthermore, NSCLC tumors that overexpress both EGFR and HER2 are more sensitive to EGFR TKIs than are tumors that overexpress EGFR but are HER2 negative. Therefore, the measurement of EGFR and HER2 protein expression and the gene copy number in NSCLC tumors may have a prognostic value in NSCLC and a predictive value for identifying patients likely to benefit from an EGFR TKI. These considerations suggest that the simultaneous inhibition of EGFR and HER2 may warrant further study in patients with NSCLC.

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“…The benefit derived from the addition of erlotinib to gemcitabine cannot be predicted based on patient characteristics as assessed by the standard processes performed in advanced and metastatic pancreatic cancer. The treatment of pancreatic cancer may be influenced by the potential of certain biomarkers to predict better response to moleculartargeted therapies (as seen in non-small cell lung cancer [NSCLC] with erlotinib and another HER-1/EGFR TKI gefitinib; also in colorectal cancer with cetuximab) [43][44][45][46][47][48][49][50][51]. The advantage of individualizing therapy to patients could be possible if we could better understand which factors predict response to treatment.…”

Section: Erlotinibmentioning

confidence: 99%

New Therapeutic Directions for Advanced Pancreatic Cancer: Targeting the Epidermal Growth Factor and Vascular Endothelial Growth Factor Pathways

Burris

Rocha-Lima

2008

The Oncologist

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After completing this course, the reader will be able to:1. Evaluate the existing chemotherapeutic options for advanced pancreatic cancer.2. Interpret data from trials of HER-1/EGFR-and VEGFR-targeted agents in advanced pancreatic cancer.3. Take advantage of the potential of biomarkers in selecting optimal molecular-targeted therapies for advanced pancreatic cancer.Access and take the CME test online and receive 1 AMA PRA Category 1 Credit ™ at CME.TheOncologist.com CME CME ABSTRACT

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Prospective Study of Gefitinib in Epidermal Growth Factor Receptor Fluorescence In Situ Hybridization–Positive/Phospho-Akt–Positive or Never Smoker Patients With Advanced Non–Small-Cell Lung Cancer: The ONCOBELL Trial

Abstract: Gefitinib is active and well tolerated in patients with trial characteristics, and EGFR FISH analysis is an accurate predictor for such therapy.

Cited by 200 publications

References 46 publications

Targeting Epidermal Growth Factor Receptor–Associated Signaling Pathways in Non–Small Cell Lung Cancer Cells: Implication in Radiation Response

Targeting Epidermal Growth Factor Receptor–Associated Signaling Pathways in Non–Small Cell Lung Cancer Cells: Implication in Radiation Response

Predictive value of EGFR and HER2 overexpression in advanced non-small-cell lung cancer

New Therapeutic Directions for Advanced Pancreatic Cancer: Targeting the Epidermal Growth Factor and Vascular Endothelial Growth Factor Pathways

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