Restoring E-Cadherin Expression Increases Sensitivity to Epidermal Growth Factor Receptor Inhibitors in Lung Cancer Cell Lines

Witta, Samir E.; Gemmill, Robert M.; Hirsch, Fred R.; Coldren, Christopher D.; Hedman, Karla; Ravdel, Larisa; Helfrich, Barbara A.; Dziadziuszko, Rafał; Chan, Daniel C.; Sugita, Michio; Zeng, Chan; Barón, Anna E.; Franklin, Wilbur A.; Drabkin, Harry A.; Girard, Luc; Gazdar, Adi F.; Minna, John D.; Bunn, Paul A.

doi:10.1158/0008-5472.can-05-1988

Cited by 462 publications

(381 citation statements)

References 43 publications

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“…17,19,20,31 Moreover, E-cadherin has been proposed as a biomarker for therapies, such as EGFR tyrosine kinase activity inhibitors or other molecules interfering with EGFR signaling. 18,32 Our study data also suggest that E-cadherin expression could be a clinically relevant biomarker for TK/GCV therapy. …”

Section: Discussionsupporting

confidence: 54%

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E-cadherin contributes to the bystander effect of TK/GCV suicide therapy and enhances its antitumoral activity in pancreatic cancer models

et al. 2010

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The thymidine kinase/ganciclovir (TK/GCV) cancer gene therapy approach is based on inducing GCV metabolite cytotoxicity in tumor cells expressing the herpes simplex virus TK gene and exposed to GCV. A bystander effect, mediated by gap junctions, accounts for the transfer of toxic metabolites from TK-expressing cells to neighboring cells. It has been proposed that E-cadherin participates in the formation and function of such gap junctions. In this study we investigate the influence of E-cadherin on TK/GCV suicide therapy with a panel of cellular and in vivo models of pancreatic ductal adenocarcinoma. We observed a strong correlation of E-cadherin expression and the TK/GCV bystander effect, associated with the modulation of gap junction communication and connexin expression or localization. Importantly, the co-expression of TK and E-cadherin genes in the adenoviral vector AdTat8TKIE improved TK/GCV cytotoxicity and triggered a potent antitumoral effect, superior to standard AdTat8TK/GCV in MIAPaCa-2 xenografts. The increased expression of E-cadherin resulted in the reduction of the bcl-2 content. Interestingly, the knockdown of bcl-2 sensitized cells to TK/GCV. Thus, we propose that by restoring E-cadherin in pancreatic tumor cells we will improve TK/GCV therapy, both by enhancing the bystander effect and by facilitating the induction of apoptosis.

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Section: Discussionsupporting

confidence: 54%

“…The central role of E-cadherin in modulating the response to a variety of different antitumoral therapies, such as, EGFR-targeted treatment, 18,19 or the chemotherapeutic agents taxol and etoposide, 17,20 has been shown. However, the ability of E-cadherin to enhance TK/GCV cytotoxicity is reported for the first time in this study.…”

Section: Discussionmentioning

confidence: 99%

E-cadherin contributes to the bystander effect of TK/GCV suicide therapy and enhances its antitumoral activity in pancreatic cancer models

et al. 2010

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“…In non-small cell lung cancer, E-cadherin has an important function in prognosis and progression and interacts with EGFR. In this neoplasia, E-cadherin and ZEB1 expression correlate with sensitivity to the EGFR inhibitor genitinib (Witta et al, 2006). Similarly, colorectal and pancreatic cell lines with mutated or no E-cadherin are also insensitive to the EGFR inhibitor erlotinib (Buck et al, 2007).…”

Section: Mutual Regulation Of Sprouty-2 and E-cadherinmentioning

confidence: 88%

SPROUTY-2 and E-cadherin regulate reciprocally and dictate colon cancer cell tumourigenicity

et al. 2010

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SPROUTY-2 (SPRY2) regulates receptor tyrosine kinase signalling and therefore cell growth and differentiation. In this study, we show that SPRY2 expression in colon cancer cells is inhibited by the active vitamin D metabolite 1a,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) through E-cadherin-dependent and -independent mechanisms. In turn, SPRY2 represses both basal and 1,25(OH) 2 D 3 -induced E-cadherin expression. In line with this, SPRY2 induces ZEB1 RNA and protein, but not that of other epithelial-to-mesenchymal transition inducers that repress the CDH1/E-cadherin promoter. Consistently, SPRY2 and E-cadherin protein levels inversely correlate in colon cancer cell lines and xenografted tumours. Moreover, SPRY2 knockdown by small hairpin RNA increases CDH1/E-cadherin expression and, reciprocally, CDH1/E-cadherin knockdown increases that of SPRY2. In colon cancer patients, SPRY2 is upregulated in undifferentiated high-grade tumours and at the invasive front of low-grade carcinomas. Quantification of protein expression in 34 tumours confirmed an inverse correlation between SPRY2 and E-cadherin. Our data demonstrate a tumourigenic action of SPRY2 that is based on the repression of E-cadherin, probably by the induction of ZEB1, and a reciprocal regulation of SPRY2 and E-cadherin that dictates cell phenotype. We propose SPRY2 as a candidate novel marker for high-grade tumours and a target of therapeutic intervention in colon cancer.

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“…It is reported that patients with phospho AKTpositive tumours had a better response rate, disease control rate, and time to progression by gefitinib treatment (Cappuzzo et al, 2004). Expression of E-cadherin, a calcium-dependent adhesion molecule, has been related to sensitivity to gefitinib (Witta et al, 2006). These lines of evidence clearly indicate that comprehensive analyses of molecular biomarkers should be carried out in conjunction with clinical trials of EGFR inhibitors.…”

Section: Biomarker For Egfr-tkimentioning

confidence: 97%

Which biomarker predicts benefit from EGFR-TKI treatment for patients with lung cancer?

Uramoto

Mitsudomi

2007

Br J Cancer

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Subsets of patients with non-small cell lung cancer respond remarkably well to small molecule tyrosine kinase inhibitors (TKI) specific for epidermal growth factor receptor (EGFR) such as gefitinib or erlotinib. In 2004, it was found that EGFR mutations occurring in the kinase domain are strongly associated with EGFR-TKI sensitivity. However, subsequent studies revealed that this relationship was not perfect and various predictive markers have been reported. These include EGFR gene copy numbers, status of ligands for EGFR, changes in other HER family genes or molecules downstream to EGFR including KRAS or AKT. In this review, we would like to review current knowledge of predictive factors for EGFR-TKI. As all but one phase III trials failed to show a survival advantage of the treatment arm involving EGFR-TKIs, it is necessary to select patients by these biomarkers in future clinical trials. Through these efforts, it would be possible to individualise EGFR-TKI treatment for patients suffering from lung cancer.

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Restoring E-Cadherin Expression Increases Sensitivity to Epidermal Growth Factor Receptor Inhibitors in Lung Cancer Cell Lines

Cited by 462 publications

References 43 publications

E-cadherin contributes to the bystander effect of TK/GCV suicide therapy and enhances its antitumoral activity in pancreatic cancer models

E-cadherin contributes to the bystander effect of TK/GCV suicide therapy and enhances its antitumoral activity in pancreatic cancer models

SPROUTY-2 and E-cadherin regulate reciprocally and dictate colon cancer cell tumourigenicity

Which biomarker predicts benefit from EGFR-TKI treatment for patients with lung cancer?

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