Abstract A159: The inherent resistant of breast cancer to EGFR-targeted therapies is driven by EMT-induced expression of particular FGFR splice variants

Michael K. Wendt; Jenny Parvani; Barbara Schiemann; Khalid Sossey-Aiaoui; William Schiemann

doi:10.1158/1535-7163.TARG-13-A159

Abstract Epithelial-mesenchymal transition (EMT) and the reverse process of mesenchymal-epithelial transition (MET) are critical processes in cancer metastasis and resistance to molecular targeted therapies. However, the molecular events that facilitate these processes remain to be fully elucidated. Using an in vivo reporter system for the promoter activity of Epithelial-Cadherin (E-cad), we quantify a robust EMT that takes place upon orthotopic engraftment of highly metastatic breast cancer cells. Moreover, using this reporter system together with immunohistochemistry we demonstrate that E-cad expression does not return until after initiation of pulmonary metastatic outgrowth. Using an epidermal growth factor receptor (EGFR)-driven model of in situ breast cancer that is highly sensitive to Erlotinib, we show that induction of EMT is sufficient to drive metastasis and that following the MET process these cells become inherently resistant to EGFR-inhibition. Microarray analyses of these cells demonstrate that following EMT:MET there is critical pathway switch from EGFR to aberrant growth factor signaling that is mediated by a truncated splice variant of fibroblast growth factor receptor 1 (FGFR1). In silico and RT-PCR analyses of patient tumor samples revealed a potent upregulation of the truncated FGFR1 isoform. Indeed, while EGFR expression is initially required for aberrant maintenance of EMT-induced FGFR expression, EGFR and several EGFR ligands are potently down regulated during the MET process. These findings are consistent with previous studies from our group and others demonstrating loss of EGFR expression in late-stage breast cancers and the clinical failure of EGFR-targeted therapies in the treatment of breast cancer. shRNA-mediated depletion of FGFR1 in an EGFR-null model of pulmonary metastatic outgrowth dramatically inhibited pulmonary tumor formation. Moreover, in vivo treatment of mice with the FGFR kinase inhibitor BGJ-398 similarly decreased pulmonary tumor outgrowth. Finally, ectopic expression of the full-length form of FGFR1 also prevented tumor outgrowth following tail vein inoculation. Overall, our data demonstrate the dynamic flux between EGFR and FGFR during particular stages of breast cancer progression. Moreover, our findings demonstrate the plausible utility of identifying truncated FGFR1 splice variants as a predictive biomarker for FGFR targeted molecular therapies. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A159. Citation Format: Michael K. Wendt, Jenny Parvani, Barbara Schiemann, Khalid Sossey-Aiaoui, William Schiemann. The inherent resistant of breast cancer to EGFR-targeted therapies is driven by EMT-induced expression of particular FGFR splice variants. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A159.

Abstract A159: The inherent resistant of breast cancer to EGFR-targeted therapies is driven by EMT-induced expression of particular FGFR splice variants

View Online

Abstract

Details

Metrics