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

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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, Stinson, Jeremy, Seshagiri, Somasekar, Modrusan, Zora, Lin, Chin-Yu, O'Neill, Vincent, Amler, Lukas C.·2005·Clinical Cancer Research

DOI 10.1158/1078-0432.ccr-05-1492

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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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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
ORCID: Yauch, Robert L.
Fu, Ling
Seshagiri, Somasekar
Modrusan, Zora
Lin, Chin-Yu
Venue: Clinical Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2005-12-15
Volume: 11
Issue: 24
Pages: 8686-8698
ISSN: 1078-0432 (ISSN-L)
1557-3265
DOI: 10.1158/1078-0432.ccr-05-1492
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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Epithelial versus Mesenchymal Phenotype Determines In vitro Sensitivity and Predicts Clinical Activity of Erlotinib in Lung Cancer Patients

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