Delta-crystallin enhancer binding factor 1 controls the epithelial to mesenchymal transition phenotype and resistance to the epidermal growth factor receptor inhibitor erlotinib in human head and neck squamous cell carcinoma lines.
OBJECTIVE
Although the epidermal growth factor receptor (EGFR) is overexpressed in a majority of head and neck squamous cell carcinomas (HNSCC), only a minority of patients derive substantial clinical benefit from EGFR inhibitors. We initiated the present study to identify the mechanisms underlying erlotinib resistance in a panel of HNSCC cell lines.


METHODS
We used [(3)H]thymidine incorporation to characterize the heterogeneity of responsiveness to erlotinib-mediated growth inhibition in a panel of 27 human HNSCC cells. We characterized the molecular mechanisms involved in resistance using a representative subset of six erlotinib-sensitive and erlotinib-resistant HNSCC lines.


RESULTS
Erlotinib had heterogeneous effects on DNA synthesis in HNSCC cells that correlated closely with molecular markers of epithelial to mesenchymal transition (EMT). Specifically, the drug-sensitive lines expressed high levels of E-cadherin and showed limited invasion and migration capabilities. In contrast, the erlotinib-resistant HNSCC lines expressed high levels of the E-cadherin repressor delta-crystallin enhancer binding factor 1 (deltaEF1; Zeb-1) and other mesenchymal markers and low levels of E-cadherin, and they were highly invasive and migratory. Small interfering RNA-mediated knockdown of deltaEF1 in the erlotinib-resistant cell lines (1386LN and UMSCC1) resulted in up-regulation of E-cadherin and increased sensitivity to erlotinib in an E-cadherin-dependent manner.


CONCLUSIONS
DeltaEF1 controls the mesenchymal phenotype and drives erlotinib resistance in HNSCC cells. E-cadherin and deltaEF1 may prove to be useful markers in predicting EGFR inhibitor responsiveness.
Haddad
Yasmine
Y
Department of Urology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Choi
Woonyoung
W
McConkey
David J
DJ
D015820:Cadherins / Q000096:biosynthesis / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004848:Epithelium / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000378:metabolism; D018398:Homeodomain Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008648:Mesoderm / Q000378:metabolism*; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D000071799:Zinc Finger E-box-Binding Homeobox 1; D038207:delta-Crystallins / Q000737:chemistry*
D015820:Cadherins; D018398:Homeodomain Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D038207:delta-Crystallins; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors