Abstract B119: Mechanisms of drug resistance to molecular target therapeutics against tyrosine kinases as EGFR, c-Met, and PDGFR in GBM.

Abstract

Abstract Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor. Despite technological advances in surgery, combined with regimens of radiotherapy and new generation chemotherapy, the median survival is still 15 months. Several molecular therapeutics targeting protein tyrosine kinases have recently been attempted; however, the emerging drug resistance is a crucial issue. Here, we established cell lines acquired drug resistance to individual inhibitor for major tyrosine kinase as EGFR, c-Met, or PDGFR that highly expressed in GBM, and characterized the underlying mechanisms. While initial 50 days starting inhibitor treatment, the cells exhibited distinct morphological changes of epithelial-mesenchymal transition (EMT) concomitant with up-regulation of Snail, Slug, and Mmp-2. Of note, further continuous drug treatment produced stemness-like properties in the cells. PCR array and microarray analysis have identified marked enhancement of several stemness-related genes including Sox2 and CXCL12. These findings show that suppression of EMT and/or stemness features of GBM may be an effective strategy to avoid the acquisition of resistance for molecular target therapy in GBM. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B119. Citation Format: Masumi Tsuda, Lei Wang, Mishie Tanino, Taichi Kimura, Hiroshi Nishihara, Shinya Tanaka. Mechanisms of drug resistance to molecular target therapeutics against tyrosine kinases as EGFR, c-Met, and PDGFR in GBM. [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 B119.