Baseline Gene Expression Predicts Sensitivity to Gefitinib in Non–Small Cell Lung Cancer Cell Lines

Coldren, Christopher D.; Helfrich, Barbara A.; Witta, Samir E.; Sugita, Michio; Lapadat, Razvan; Zeng, Chan; Barón, Anna E.; Franklin, Wilbur A.; Hirsch, Fred R.; Geraci, Mark W.; Bunn, Paul A.

doi:10.1158/1541-7786.mcr-06-0095

Cited by 126 publications

(125 citation statements)

References 36 publications

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“…The nimotuzumab-resistant cell line H460 harbours a mutant form of KRAS (Balko et al, 2006) that has been associated with resistance to cetuximab (Lievre et al, 2006). However, we found that nimotuzumab also failed to inhibit EGF-induced EGFR phosphorylation and to enhance the cytotoxic effect of radiation in H1299 cells, which harbour wild-type KRAS (Coldren et al, 2006). These observations thus support the notion that a low level of EGFR expression at the cell surface is related to resistance to combined treatment with nimotuzumab and radiation, irrespective of KRAS status.…”

Section: Discussionmentioning

confidence: 57%

Enhancement of the antitumor activity of ionising radiation by nimotuzumab, a humanised monoclonal antibody to the epidermal growth factor receptor, in non-small cell lung cancer cell lines of differing epidermal growth factor receptor status

et al. 2008

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The expression and activity of the epidermal growth factor receptor (EGFR) are determinants of radiosensitivity in several tumour types, including non-small cell lung cancer (NSCLC). However, little is known of whether genetic alterations of EGFR in NSCLC cells affect the therapeutic response to monoclonal antibodies (mAbs) to EGFR in combination with radiation. We examined the effects of nimotuzumab, a humanised mAb to EGFR, in combination with ionising radiation on human NSCLC cell lines of differing EGFR status. Flow cytometry revealed that H292 and Ma-1 cells expressed high and moderate levels of EGFR on the cell surface, respectively, whereas H460, H1299, and H1975 cells showed a low level of surface EGFR expression. Immunoblot analysis revealed that EGFR phosphorylation was inhibited by nimotuzumab in H292 and Ma-1 cells but not in H460, H1299, or H1975 cells. Nimotuzumab augmented the cytotoxic effect of radiation in H292 and Ma-1 cells in a clonogenic assay in vitro, with a dose enhancement factor of 1.5 and 1.3, respectively. It also enhanced the antitumor effect of radiation on H292 and Ma-1 cell xenografts in nude mice, with an enhancement factor of 1.3 and 4.0, respectively. Nimotuzumab did not affect the radioresponse of H460 cells in vitro or in vivo. Nimotuzumab enhanced the antitumor efficacy of radiation in certain human NSCLC cell lines in vitro and in vivo. This effect may be related to the level of EGFR expression on the cell surface rather than to EGFR mutation.

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Section: Discussionmentioning

confidence: 57%

Enhancement of the antitumor activity of ionising radiation by nimotuzumab, a humanised monoclonal antibody to the epidermal growth factor receptor, in non-small cell lung cancer cell lines of differing epidermal growth factor receptor status

et al. 2008

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“…Second, the genes and proteins involved in primary resistance to EGFR-TKIs are not well defined. We undertook genomic and proteomic approaches to determine differentially expressed genes and proteins in the sensitive compared with the resistant cell lines from this study (32).…”

Section: Discussionmentioning

confidence: 99%

Antitumor Activity of the Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor Gefitinib (ZD1839, Iressa) in Non–Small Cell Lung Cancer Cell Lines Correlates with Gene Copy Number and EGFR Mutations but not EGFR Protein Levels

Helfrich

Raben

Varella‐Garcia

et al. 2006

Clinical Cancer Research

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115

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Purpose: Recognition that the epidermal growth factor receptor (EGFR) was a therapeutic target in non^small cell lung cancer (NSCLC) and other cancers led to development of the smallmolecule receptor tyrosine kinase inhibitors gefitinib and erlotinib. Clinical trials established that EGFR tyrosine kinase inhibitors produced objective responses in a minority of NSCLC patients. We examined the sensitivity of 23 NSCLC lines with wild-type or mutated EGFR to gefitinib to determine genes/proteins related to sensitivity, including EGFR and HER2 cell surface expression, phosphorylated EGFR expression, EGFR gene copy number, and EGFR mutational status. Downstream cell cycle and signaling events were compared with growth-inhibitory effects. Experimental Design: We determined gefitinib sensitivity by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, EGFR expression by fluorescence-activated cell sorting and immunohistochemistry, phosphorylated EGFR by Western blotting, EGFR gene copy number by fluorescence in situ hybridization, and EGFR mutation by sequencing. The cellular effects of gefitinib on cell cycle were determined by flow cytometry and the molecular effects of gefitinib EGFR inhibition on downstream signal proteins by Western blotting. Gefitinib in vivo effects were evaluated in athymic nude mice bearing sensitive and resistant NSCLC xenografts. Results: There was a significant correlation between EGFR gene copy number, EGFR gene mutations, and gefitinib sensitivity. EGFR protein was necessary but not sufficient for predicting sensitivity. Gefitinib-sensitive lines showed a G 1 cell cycle arrest and inactivation of downstream signaling proteins; resistant cell lines had no changes.The in vivo effects mirrored the in vitro effects. Conclusions:This panel of NSCLC lines characterized for gefitinib response was used to identify predictive molecular markers of response to gefitinib. Several of these have subsequently been shown to identify NSCLC patients likely to benefit from gefitinib therapy.

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“…We analyzed 3 public gene expression profile (GEP) microarray datasets: the GSE12276 dataset consisting of 204 primary breast cancer specimens from patients with metastatic disease (31); the GSE5851 dataset consisting of 80 colorectal cancer specimens taken from patients prior to treatment with cetuximab (39); and the GSE4342 dataset consisting of a panel of NSCLC cell lines analyzed for sensitivity to and resistance against gefitinib treatment (41). All datasets were retrieved from the Gene Expression Omnibus (GEO) database and processed using R scripting as previously described (65).…”

Section: Methodsmentioning

confidence: 99%

“…For the GSE4342 dataset, we analyzed the expression levels of PRL-3 in NSCLC cell lines (listed in Table 1 of the original publication; ref. 41) according to the references' designation of gefitinib-sensitive (IC50 ≤4.5 μmol/l, n = 15) or gefitinib-resistant (IC50 >4.5 μmol/l, n = 12).…”

Section: Methodsmentioning

confidence: 99%

Metastasis-associated PRL-3 induces EGFR activation and addiction in cancer cells

et al. 2013

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Metastasis-associated phosphatase of regenerating liver-3 (PRL-3) has pleiotropic effects in driving cancer progression, yet the signaling mechanisms of PRL-3 are still not fully understood. Here, we provide evidence for PRL-3-induced hyperactivation of EGFR and its downstream signaling cascades in multiple human cancer cell lines. Mechanistically, PRL-3-induced activation of EGFR was attributed primarily to transcriptional downregulation of protein tyrosine phosphatase 1B (PTP1B), an inhibitory phosphatase for EGFR. Functionally, PRL-3-induced hyperactivation of EGFR correlated with increased cell growth, promigratory characteristics, and tumorigenicity. Moreover, PRL-3 induced cellular addiction to EGFR signaling, as evidenced by the pronounced reversion of these oncogenic attributes upon EGFR-specific inhibition. Of clinical significance, we verified elevated PRL-3 expression as a predictive marker for favorable therapeutic response in a heterogeneous colorectal cancer (CRC) patient cohort treated with the clinically approved anti-EGFR antibody cetuximab. The identification of PRL-3-driven EGFR hyperactivation and consequential addiction to EGFR signaling opens new avenues for inhibiting PRL-3-driven cancer progression. We propose that elevated PRL-3 expression is an important clinical predictive biomarker for favorable anti-EGFR cancer therapy.

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Baseline Gene Expression Predicts Sensitivity to Gefitinib in Non–Small Cell Lung Cancer Cell Lines

Abstract: Tyrosine kinase inhibitors

Cited by 126 publications

References 36 publications

Enhancement of the antitumor activity of ionising radiation by nimotuzumab, a humanised monoclonal antibody to the epidermal growth factor receptor, in non-small cell lung cancer cell lines of differing epidermal growth factor receptor status

Enhancement of the antitumor activity of ionising radiation by nimotuzumab, a humanised monoclonal antibody to the epidermal growth factor receptor, in non-small cell lung cancer cell lines of differing epidermal growth factor receptor status

Antitumor Activity of the Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor Gefitinib (ZD1839, Iressa) in Non–Small Cell Lung Cancer Cell Lines Correlates with Gene Copy Number and EGFR Mutations but not EGFR Protein Levels

Metastasis-associated PRL-3 induces EGFR activation and addiction in cancer cells

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