Dual MET and SMO Negative Modulators Overcome Resistance to EGFR Inhibitors in Human Nonsmall Cell Lung Cancer

5 years ago

Dual MET and SMO Negative Modulators Overcome Resistance to EGFR Inhibitors in Human Nonsmall Cell Lung Cancer

Fortunato Ciardiello, Maria Letizia Trincavelli, Carminia Maria Della Corte, Claudia Martini, Luciana Marinelli, Anna Messere, Sabrina Taliani, Vincenza Ciaramella, Sandro Cosconati, Salvatore Di Maro, Floriana Morgillo, Lorenzo Botta, Chiara Giacomelli, Ettore Novellino, Giorgio Amendola

Tyrosine kinase inhibitors (TKIs) of the EGF receptor (EGFR) have provided a significant improvement in the disease outcome of nonsmall cell lung cancer (NSCLC). Unfortunately, resistance to these agents frequently occurs, and it is often related to the activation of the Hedgehog (Hh) and MET signaling cascades driving the epithelial-to-mesenchymal transition (EMT). Because the concomitant inhibition of both Hh and MET pathways restores the sensitivity to anti-EGFR drugs, here we aimed at discovering the first compounds that block simultaneously MET and SMO. By using an “in silico drug repurposing” approach and by validating our predictions both in vitro and in vivo, we identified a set of compounds with the desired dual inhibitory activity and enhanced antiproliferative activity on EGFR TKI-resistant NSCLC. The identification of the known MET TKIs, glesatinib and foretinib, as negative modulators of the Hh pathway, widens their application in the context of NSCLC.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00794

DOI: 10.1021/acs.jmedchem.7b00794