We have previously found that Hedgehog pathway plays an important role in mediating resistance to first, second and third generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), suggesting new potential strategies of combination of novel generation EGFR-TKIs with Hedgehog inhibitors to prevent the occurrence of resistance in T790M + tumors.
H1975-AFAR and –OSIR NSCLC cell lines, harboring both the EGFR activating (L858R) and the resistant (T790M) mutations at baseline, were developed in vivo by continuos treatment with afatinib and osimertinib respectively. Both cell lines presented also the SMO V404M mutation after acquisition of resistance. These cell lines were used to test the efficacy of osimertinib or afatinib in combination with the selective SMO inhibitor, LDE225.
Treatment with each EGFR-TKIs in combination with LDE225 resulted in a significant inhibition of cell proliferation and a strong induction of apoptosis as compared to single agent treatment. Additionally, combined treatment significantly decreased the invasive and migratory abilities of resistant cells. The combination of osimertinib and LDE225 appeared to be the most effective in reverting resistance to EGFR-TKIs. Combined treatment caused regression of tumor growth in vivo in nude mice.
Our study further support the role of Hedgehog pathway activation as an important mediator of resistance to EGFR targeting drugs, also in the T790M scenario. In addition, it demonstrates that addition of a hedgehog inhibitor to an EGFR-TKI in tumors, which had developed resistance to third generation inhibitors, provides meaningful responses.
Clinical trial identification
Legal entity responsible for the study
Second University of Naples
All authors have declared no conflicts of interest.