Cited by 497Lung Cancer Treatments and MutationsHER2/EGFR in Cancer ResearchCancer Cells and Metastasis

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

Yauch, Robert L., Januario, Thomas, Eberhard, David A., Cavet, Guy, Zhu, Wenjing, Fu, Ling, Pham, Thinh Q., Soriano, Robert +6 more·2005·Clinical Cancer Research

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.

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Crossref · 10.1158/1078-0432.ccr-05-1492

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  • In the TRIBUTE trial, among patients receiving erlotinib and chemotherapy, time to progression was longer for those with E-cadherin-positive staining.

    “In the Tarceva Responses in conjunction with Paclitaxel and Carboplatin (TRIBUTE) trial,38 among patients receiving erlotinib and chemotherapy, time to progression was longer for those with E-cadherin-positive staining.39”

    From Mechanisms of resistance to EGFR-targeted drugs: lung cancer (2016) · cites this paper as [39]

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Authors
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., O'Neill, V., & Amler, L. C.
Affiliations
  • Genentech (US)
  • 5BioOncology, Genentech, Inc., South San Francisco, California
Venue
Clinical Cancer Research
Published
2005-12-15
Volume
11
Issue
24
Pages
8686-8698
ISSN
  • 1078-0432 (ISSN-L)
  • 1557-3265
OpenAlex
W2111599976
Cited by
495
References
45
Citations by year
2026: 4 · 2025: 6 · 2023: 12 · 2022: 7 · 2021: 15 · 2020: 15 · 2019: 15 · 2018: 21 · 2017: 41 · 2016: 29 · 2015: 27 · 2014: 35 · 2013: 50 · 2012: 36
FWCI
21.12
Type
journal article
Language
en
Open access
closed
Locations
  • Clinical Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • U.S. Food and Drug Administration
  • Division of Materials Research
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Keywords
erlotinib, non-small cell lung cancer, epithelial-mesenchymal transition, E-cadherin, EGFR inhibitors, predictive biomarkers, pharmacogenomics, EGFR mutation, EGFR amplification, vimentin, time to progression, combination chemotherapy
MeSH terms
Erlotinib Hydrochloride, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Epithelium, Gene Amplification, Humans, Immunohistochemistry, Lung Neoplasms, Mesoderm, Mutation, Pharmacogenetics, Phenotype, Quinazolines, Biomarkers, Tumor, Vimentin, Cadherins, Treatment Outcome, Drug Resistance, Neoplasm, Oligonucleotide Array Sequence Analysis, Cell Line, Tumor, Protein Kinase Inhibitors, Cell Proliferation, Genes, Neoplasm, ErbB Receptors

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