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An epithelial-mesenchymal transition (EMT) gene signature predicts resistance to erlotinib and PI3K pathway inhibitors and identifies Axl as a novel EMT marker in non-small cell lung cancer.

ABSTRACT: Epithelial/mesenchymal transition (EMT) is associated with loss of cell adhesion molecules, such as E-cadherin, and increased invasion, migration, and proliferation in epithelial cancers. In non-small cell lung cancer (NSCLC), EMT is associated with greater resistance to EGFR inhibitors. However, its potential to predict response to other targeted drugs or chemotherapy has not been well characterized. The goal of this study was to develop a robust, platform-independent EMT gene expression signature and to investigate the association of EMT and drug response in NSCLC. A 76-gene EMT signature was derived in 54 DNA-fingerprinted NSCLC cell lines and tested in an independent set of cell lines and in NSCLC patients from the BATTLE clinical trial. The signature classified cell lines as epithelial or mesenchymal independent of the microarray platform and correlated strongly with E-cadherin protein levels, as measured by reverse phase protein array. Higher protein expression of Rab25 (in epithelial lines) and Axl (in mesenchymal lines), two signature genes associated with in EMT in other cancer types, was also confirmed. Mesenchymal cell lines demonstrated significantly greater resistance to EGFR inhibition, independent of EGFR mutation status and were more resistant to drugs targeting the PI3K/Akt pathway. We observed no association between EMT and response to cytotoxic chemotherapies, including cisplatin, pemetrexed, and docetaxel monotherapy and/or doublets (p-values ≥0.2). In NSCLC patients, the EMT signature predicted 8-week disease control in the erlotinib arm, but not in other treatment arms. In conclusion, we have developed a robust EMT signature that predicts resistance to EGFR inhibitors and PI3K/Akt pathway inhibitors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE33072 | GEO | 2012/10/25

SECONDARY ACCESSION(S): PRJNA149495

REPOSITORIES: GEO

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Project description:Epithelial/mesenchymal transition (EMT) is associated with loss of cell adhesion molecules, such as E-cadherin, and increased invasion, migration, and proliferation in epithelial cancers. In non-small cell lung cancer (NSCLC), EMT is associated with greater resistance to EGFR inhibitors. However, its potential to predict response to other targeted drugs or chemotherapy has not been well characterized. The goal of this study was to develop a robust, platform-independent EMT gene expression signature and to investigate the association of EMT and drug response in NSCLC. A 76-gene EMT signature was derived in 54 DNA-fingerprinted NSCLC cell lines and tested in an independent set of cell lines and in NSCLC patients from the BATTLE clinical trial. The signature classified cell lines as epithelial or mesenchymal independent of the microarray platform and correlated strongly with E-cadherin protein levels, as measured by reverse phase protein array. Higher protein expression of Rab25 (in epithelial lines) and Axl (in mesenchymal lines), two signature genes associated with in EMT in other cancer types, was also confirmed. Mesenchymal cell lines demonstrated significantly greater resistance to EGFR inhibition, independent of EGFR mutation status and were more resistant to drugs targeting the PI3K/Akt pathway. We observed no association between EMT and response to cytotoxic chemotherapies, including cisplatin, pemetrexed, and docetaxel monotherapy and/or doublets (p-values ≥0.2). In NSCLC patients, the EMT signature predicted 8-week disease control in the erlotinib arm, but not in other treatment arms. In conclusion, we have developed a robust EMT signature that predicts resistance to EGFR inhibitors and PI3K/Akt pathway inhibitors. Gene expression profiles were measured in 131 core biopsies from patients with refractory non-small cell lung cancer in the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial. We used the BATTLE dataset to test an EMT gene expression signature trained in cell lines and independant of the microarray platform.

Project description:Despite initial and often dramatic responses of epidermal growth factor receptor (EGFR)-addicted lung tumors to the EGFR-specific tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, nearly all develop resistance and relapse. To explore novel mechanisms mediating acquired resistance, we employed non-small-cell lung cancer (NSCLC) cell lines bearing activating mutations in EGFR and rendered them resistant to EGFR-specific TKIs through chronic adaptation in tissue culture. In addition to previously observed resistance mechanisms including EGFR-T790M 'gate-keeper' mutations and MET amplification, a subset of the seven chronically adapted NSCLC cell lines including HCC4006, HCC2279 and H1650 cells exhibited marked induction of fibroblast growth factor (FGF) 2 and FGF receptor 1 (FGFR1) mRNA and protein. Also, adaptation to EGFR-specific TKIs was accompanied by an epithelial to mesenchymal transition (EMT) as assessed by changes in CDH1, VIM, ZEB1 and ZEB2 expression and altered growth properties in Matrigel. In adapted cell lines exhibiting increased FGF2 and FGFR1 expression, measures of growth and signaling, but not EMT, were blocked by FGFR-specific TKIs, an FGF-ligand trap and FGFR1 silencing with RNAi. In parental HCC4006 cells, cell growth was strongly inhibited by gefitinib, although drug-resistant clones progress within 10 days. Combined treatment with gefitinib and AZD4547, an FGFR-specific TKI, prevented the outgrowth of drug-resistant clones. Thus, induction of FGF2 and FGFR1 following chronic adaptation to EGFR-specific TKIs provides a novel autocrine receptor tyrosine kinase-driven bypass pathway in a subset of lung cancer cell lines that are initially sensitive to EGFR-specific TKIs. The findings support FGFR-specific TKIs as potentially valuable additions to existing targeted therapeutic strategies with EGFR-specific TKIs to prevent or delay acquired resistance in EGFR-driven NSCLC. Examination of mRNA levels in DMSO and gefitinib-resistant cultures of HCC4006 and HCC827. Each group has two replicates.

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An epithelial-mesenchymal transition (EMT) gene signature predicts resistance to erlotinib and PI3K pathway inhibitors and identifies Axl as a novel EMT marker in non-small cell lung cancer.

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