DOI: 10.1158/1078-0432.ccr-05-1492. Epithelial versus Mesenchymal Phenotype Determines <i>In vitro</i> Sensitivity and Predicts Clinical Activity of Erlotinib in Lung Cancer Patients

Epithelial versus Mesenchymal Phenotype Determines In vitro Sensitivity and Predicts Clinical Activity of Erlotinib in Lung Cancer Patients

10.1158/1078-0432.ccr-05-1492

Crossref journal-article

American Association for Cancer Research (AACR)

Clinical Cancer Research (1086)

Abstract

Abstract Significant improvements in the outcome of non–small cell lung carcinoma (NSCLC) have been reported in patients treated with the epidermal growth factor receptor (EGFR) inhibitor, erlotinib. To discover biomarkers for the enrichment of patients who might benefit from treatment, a pharmacogenomic approach was used to identify gene signatures that may predict erlotinib activity using in vitro model systems. Erlotinib sensitivity in a panel of 42 NSCLC cell lines was determined by EGFR-mediated proliferative potential, EGFR mutations, and/or EGFR gene amplification, thus supporting an underlying biological mechanism of receptor activation. A strong multigene signature indicative of an epithelial to mesenchymal transition (EMT) was identified as a determinant of insensitivity to erlotinib through both supervised and unsupervised gene expression approaches. This observation was further supported by expression analysis of classic EMT marker proteins, including E-cadherin and vimentin. To investigate the clinical relevance of these findings, we examined expression of the epithelial marker E-cadherin by immunohistochemistry on primary tumor samples from subjects enrolled in a randomized NSCLC clinical trial in which erlotinib in combination with chemotherapy previously failed to show clinical activity. The majority (75%) of the 87 subjects tested showed strong E-cadherin staining and exhibited a significantly longer time to progression (hazard ratio, 0.37; log rank P = 0.0028) and a nonsignificant trend toward longer survival with erlotinib plus chemotherapy treatment versus chemotherapy alone. These data support a potential role for EMT as a determinant of EGFR activity in NSCLC tumor cells and E-cadherin expression as a novel biomarker predicting clinical activity of the EGFR inhibitor erlotinib in NSCLC patients.

Bibliography

Yauch, R. L., Januario, T., Eberhard, D. A., Cavet, G., Zhu, W., Fu, L., Pham, T. Q., Soriano, R., Stinson, J., Seshagiri, S., Modrusan, Z., Lin, C.-Y., OâNeill, V., & Amler, L. C. (2005). Epithelial versus Mesenchymal Phenotype Determines In vitro Sensitivity and Predicts Clinical Activity of Erlotinib in Lung Cancer Patients. Clinical Cancer Research, 11(24), 8686â8698.

Authors 14

Robert L. Yauch (first)
Thomas Januario (additional)
David A. Eberhard (additional)
Guy Cavet (additional)
Wenjing Zhu (additional)
Ling Fu (additional)
Thinh Q. Pham (additional)
Robert Soriano (additional)
Jeremy Stinson (additional)
Somasekar Seshagiri (additional)
Zora Modrusan (additional)
Chin-Yu Lin (additional)
Vincent O'Neill (additional)
Lukas C. Amler (additional)

References 42 Referenced 416

Dates

Type	When
Created	19 years, 5 months ago (March 21, 2006, 1:43 p.m.)
Deposited	3 years, 2 months ago (June 11, 2022, 3:12 p.m.)
Indexed	5 days, 2 hours ago (Aug. 31, 2025, 6:23 a.m.)
Issued	19 years, 8 months ago (Dec. 15, 2005)
Published	19 years, 8 months ago (Dec. 15, 2005)
Published Online	19 years, 8 months ago (Dec. 16, 2005)
Published Print	19 years, 8 months ago (Dec. 15, 2005)

Funders 0

None

BibTeX

@article{Yauch_2005, title={Epithelial versus Mesenchymal Phenotype Determines In vitro Sensitivity and Predicts Clinical Activity of Erlotinib in Lung Cancer Patients}, volume={11}, ISSN={1557-3265}, url={http://dx.doi.org/10.1158/1078-0432.ccr-05-1492}, DOI={10.1158/1078-0432.ccr-05-1492}, number={24}, journal={Clinical Cancer Research}, publisher={American Association for Cancer Research (AACR)}, author={Yauch, Robert L. and Januario, Thomas and Eberhard, David A. and Cavet, Guy and Zhu, Wenjing and Fu, Ling and Pham, Thinh Q. and Soriano, Robert and Stinson, Jeremy and Seshagiri, Somasekar and Modrusan, Zora and Lin, Chin-Yu and O’Neill, Vincent and Amler, Lukas C.}, year={2005}, month=dec, pages={8686–8698} }

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