Effect of GDC-0449, a hedgehog (Hh) pathway inhibitor, on tumor activity and on erlotinib and cisplatin in a xenograft model of non-small cell lung cancer (NSCLC) with activated Hh pathway.

e21057 Background: We have previously shown that chronic exposure of A549 NSCLC cell line to TGF-β1 can induce epithelial-mesenchymal transition (EMT) and can make these cell lines (A549-M) resistant to erlotinib, an EGFR inhibitor and cisplatin. EMT in A549-M cells was associated with significant activation of signaling through the Hh pathway. We therefore evaluated the activity of GDC-0449, an inhibitor of the Hh pathway, and assessed its activity in combination with erlotinib and cisplatin in A549-M cells both in vitro and in vivo. Methods: We assessed the effects of GDC-0449 (20 nM) on clonogenic growth (colony formation assay), cell motility (wound healing assay) and invasion (matrigel assay) in A549-M cells, and also assessed the activity of GDC-0449 in combination with erlotinib and cisplatin both in vitro (MTT assay) and in an experimental lung metastasis animal model in vivo by injecting A549-M cells through tail vein. Results: A549-M cells showed significantly higher rate of clonogenic growth, c...