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Human Mena^+11a Isoform Serves as a Marker of Epithelial Phenotype and Sensitivity to Epidermal Growth Factor Receptor Inhibition in Human Pancreatic Cancer Cell Lines

Authors' Affiliations: ¹ Division of Medical Oncology, Laboratories of ² Immunology, ³ Experimental Chemotherapy, and ⁴ Pathology, Regina Elena National Cancer Institute, Rome, Italy; ⁵ Proteome Biochemistry, Dibit, San Raffaele Scientific Institute, Milan, Italy; ⁶ Department of Cancer Biology, The University of Texas, M. D. Anderson Cancer Center, Houston, Texas; and ⁷ David H. Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, Cambridge, Massachusetts

Requests for reprints: Paola Nisticò, Laboratory of Immunology, Regina Elena National Cancer Institute, Via delle Messi d'Oro 156, 00158 Rome, Italy. Phone: 39-06-52662539; Fax: 39-06-52662539; E-mail: nistico{at}ifo.it.

Purpose: hMena, member of the enabled/vasodilator-stimulated phosphoprotein family, is a cytoskeletal protein that is involved in the regulation of cell motility and adhesion. The aim of this study was to determine whether or not the expression of hMena isoforms correlated with sensitivity to EGFR tyrosine kinase inhibitors and could serve as markers with potential clinical use.

Experimental Design: Human pancreatic ductal adenocarcinoma cell lines were characterized for in vitro sensitivity to erlotinib, expression of HER family receptors, markers of epithelial to mesenchymal transition, and expression of hMena and its isoform hMena^+11a. The effects of epidermal growth factor (EGF) and erlotinib on hMena expression as well as the effect of hMena knockdown on cell proliferation were also evaluated.

Results: hMena was detected in all of the pancreatic tumor cell lines tested as well as in the majority of the human tumor samples [primary (92%) and metastatic (86%)]. Intriguingly, in vitro hMena^+11a isoform was specifically associated with an epithelial phenotype, EGFR dependency, and sensitivity to erlotinib. In epithelial BxPC3 cells, epidermal growth factor up-regulated hMena/hMena^+11a and erlotinib down-regulated expression. hMena knockdown reduced cell proliferation and mitogen-activated protein kinase and AKT activation in BxPC3 cells, and promoted the growth inhibitory effects of erlotinib.

Conclusions: Collectively, our data indicate that the hMena^+11a isoform is associated with an epithelial phenotype and identifies EGFR-dependent cell lines that are sensitive to the EGFR inhibitor erlotinib. The availability of anti-hMena^+11a–specific probes may offer a new tool in pancreatic cancer management if these results can be verified prospectively in cancer patients.