Analysis of epidermal growth factor receptor expression as a predictive factor for response to gefitinib (‘Iressa’, ZD1839) in non-small-cell lung cancer

Parra, H. Soto; Cavina, Raffaele; Latteri, F; Zucali, Paolo Andrea; Campagnoli, Elisabetta; Morenghi, Emanuela; Grimaldi, Gabriela; Roncalli, Massimo; Santoro, Armando

doi:10.1038/sj.bjc.6601923

Cited by 188 publications

(112 citation statements)

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“…The gefitinib concentration of 1 M was used as cutoff for sensitivity because this concentration approaches levels observed in serum from patients under treatment with 250 mg/day [6]. In line with other reports [28,33,34] no association between responsiveness to gefitinib and EGFR level was observed.…”

Section: Discussionmentioning

confidence: 59%

Everolimus restores gefitinib sensitivity in resistant non-small cell lung cancer cell lines

Monica

Galetti

Alfieri

et al. 2009

Biochemical Pharmacology

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 ABSTRACTThe epidermal growth factor receptor (EGFR) is a validated target for therapy in non-small cell lung cancer (NSCLC). Most patients, however, either do not benefit or develop resistance to specific inhibitors of the EGFR tyrosine kinase activity, such as gefitinib or erlotinib. The mammalian target of rapamycin (mTOR) is a key intracellular kinase integrating proliferation and survival pathways and has been associated with resistance to EGFR tyrosine kinase inhibitors. In this study, we assessed the effects of combining the mTOR inhibitor everolimus (RAD001) with gefitinib on a panel of NSCLC cell lines characterized by gefitinib-resistance and able to maintain pS6K phosphorylation after gefitinib treatment.Everolimus plus gefitinib induced a significant decrease in the activation of MAPK and mTOR signaling pathways downstream of EGFR and resulted in a growth-inhibitory effect rather than in an enhancement of cell death. A synergistic effect was observed in those cell lines characterized by high proliferative index and low doubling time. These data suggest that treatment with everolimus and gefitinib might be of value in the treatment of selected NSCLC patients that exhibit high tumor proliferative activity.

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Section: Discussionmentioning

confidence: 59%

Everolimus restores gefitinib sensitivity in resistant non-small cell lung cancer cell lines

Monica

Galetti

Alfieri

et al. 2009

Biochemical Pharmacology

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“…Indeed, although some authors reported a relationship between EGFR protein expression assessed by IHC and clinical benefit from EGFR tyrosine kinase inhibitors in NSCLC, 13,14 such a correlation was not confirmed by others. 11,36,37 Therefore, the predictive value of EGFR IHC in NSCLC care remains to be validated.…”

Section: Discussionmentioning

confidence: 99%

EGFR and KRAS status of primary sarcomatoid carcinomas of the lung: Implications for anti‐EGFR treatment of a rare lung malignancy

Italiano

Cortot

Ilié

et al. 2009

Intl Journal of Cancer

103

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Sarcomatoid carcinomas (SC) of the lung are uncommon malignant tumors composed of carcinomatous and sarcomatous cell components and characterized by a more aggressive outcome than other histological subtypes of nonsmall cell lung cancer (NSCLC). Although epidermal growth factor receptor (EGFR)‐targeted therapies have emerged as a promising therapeutic approach in patients with advanced typical NSCLC such as adenocarcinoma, the potential clinical activity of these drugs in lung SC is still unknown. To investigate this point, we have analyzed the status of 4 EGFR pathways biomarkers in a series of lung SC. EGFR protein expression, EGFR gene copy number, EGFR mutational status and KRAS mutational status were assessed in a series of 22 consecutive cases of primary lung SC. EGFR protein overexpression was observed in all the cases. High level of polysomy (≥4 copies of the gene in >40% of cells) was detected in 5 cases (23%). No EGFR mutation was detected. KRAS mutations were found in 8 patients (38%; Gly12Cys in 6 cases and Gly12Val in 2 cases). The consistent EGFR protein overexpression and the high rate of KRAS mutation may contribute to the poorer outcome of lung SC in comparison with typical NSCLC. The rare incidence of increased EGFR gene copy number, the lack of EGFR mutation and the high rate of KRAS mutation observed in our series also suggest that most patients with lung SC are not likely to benefit from anti‐EGFR therapies. © 2009 UICC

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“…Initial studies that evaluated EGFR status by immunohistochemistry did not show any correlation between levels of EGFR protein expression and response to gefitinib or erlotinib. [13][14][15] However, closer analysis of the small subset of responders revealed several themes. Patients who responded to gefitinib tended to be female, Japanese, nonsmokers, and those diagnosed with a particular type of NSCLC termed bronchioalveolar carcinoma (BAC).…”

mentioning

confidence: 99%

Biomarkers to Predict Response to Epidermal Growth Factor Receptor Inhibitors

Haas‐Kogan¹,

Prados²,

Lamborn³

et al. 2005

Cell Cycle

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Analysis of epidermal growth factor receptor expression as a predictive factor for response to gefitinib (‘Iressa’, ZD1839) in non-small-cell lung cancer

Cited by 188 publications

References 20 publications

Everolimus restores gefitinib sensitivity in resistant non-small cell lung cancer cell lines

Everolimus restores gefitinib sensitivity in resistant non-small cell lung cancer cell lines

EGFR and KRAS status of primary sarcomatoid carcinomas of the lung: Implications for anti‐EGFR treatment of a rare lung malignancy

Biomarkers to Predict Response to Epidermal Growth Factor Receptor Inhibitors

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