Co-Activation of Hedgehog and Met Pathways in Mediating Resistance to Gefitinib in Non-Small Cell Lung Cancer Cell Line Harboring Activating Mutation of Egfr

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ABSTRACT Aim: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective treatments in the management of patients harboring EGFR activating mutations. However, all initially responsive patients experience relapse as a result of acquired drug resistance. The epithelial-to-mesencymal transition (EMT) is a critical event in the development of metastases and represents an important mechanism of acquired resistance to molecularly targeted agents in non-small cel lung cancer (NSCLC). Among the various molecular pathways, the Hedgehog (Hh) signaling cascade has emerged as an important mediator of EMT. Methods: We studied the activation of Hh signaling in a NSCLC model of acquired resistance to gefitinib (HCC827-GR) obtained from a cell line harboring an activating mutation (del exon 19) of EGFR (HCC827). Results: HCC827-GR cells displayed an EMT phenotype, along with higher expression aand increased activation of MET, MAPK and AKT. Asignificantly increased expression of Shh, Smo and Gli1 mRNAs and proteins were evidenced as compared to parental HCC827 cells. Combined inhibition of MET and Hh pathways strongly inhibited cell proliferation, migration, invasion, reverted the mesenchymal phenotype and induced apoptosis at higher level than single inhibition of each pathway. MET and Smo proteins co-precipitated in HCC827-GR cells suggesting a reciprocal activation with a canonical activation of Gli1. Furthermore, MET inhibition strongly reduced Gli1 trascriptional activity, indicating a direct activity of MET-activated downstream pathways on Gli1 activation suggetsing also a cMET-mediated non canonical activation of Gli1. Conclusions: Our data suggest that both MET and Hh pathways provide alternative proliferation and survival mechanisms for NSCLC cancer cells harboring EGFR activating mutations in which EGFR is blocked by gefitinib. Disclosure: All authors have declared no conflicts of interest.