SMO gene amplification and activation of the hedgehog pathway as novel mechanisms of resistance to anti-epidermal growth factor receptor drugs in human lung cancer
Menée sur des lignées cellulaires de cancer du poumon non à petites cellules, cette étude met en évidence des mécanismes par lesquels, en induisant une transition épithélio-mésenchymateuse, l'amplification du gène SMO et la voie de signalisation Hedgehog favorisent une résistance aux thérapies ciblées anti EGFR
Purpose: Resistance to tyrosine kinase inhibitors (TKIs) of epidermal growth factor receptor (EGFR) is often related to activation of other signaling pathways and evolution through a mesenchymal phenotype. Experimental Design: Since Hedgehog (Hh) pathway has emerged as an important mediator of epithelial-to-mesenchymal transition (EMT), we studied the activation of Hh signaling in models of EGFR TKIs intrinsic or acquired resistance from both EGFR mutated and wild-type (WT) non small cell lung cancer (NSCLC) cell lines. Results: Activation of the Hh pathway was found in both models of EGFR-mutated and EGFR-WT NSCLC cell line resistant to EGFR-TKIs. In EGFR mutated HCC827-GR cells we found SMO (the Hh receptor) gene amplification, MET activation and the functional interaction of these two signaling pathways. In HCC827-GR cells inihibition of SMO or downregulation of GLI1 (the most important Hh-induced transcription factor) expression in combination with MET inhibition exerted significant antitumor activity. In EGFR-WT NSCLC cell lines resistant to EGFR inhibitors, the combined inhibition of SMO and EGFR exerted a strong antiproliferative activity with a complete inhibition of PI3K/Akt and MAPK phosphorylation. Additionally, the inhibition of SMO by the use of LDE225 sensitizes EGFR WT NSCLC cells to standard chemotherapy. Conclusions: This results support the role of Hh pathway in mediating resistance to anti-EGFR TKIs through the induction of EMT and suggests new opportunities to design new treatment strategies in lung cancer.