Elucidating the mechanisms of acquired resistance in lung adenocarcinomas

摘要: In EGFR mutant lung adenocarcinomas, targeted therapy with the EGFR tyrosine kinase inhibitors (TKIs) erlotinib, gefitinib, and afatinib performs better than standard chemotherapy in terms of progression free survival (PFS) and radiographic response (RR) rates. In the ALK rearranged cases, targeted therapy with crizotinib is associated with PFS of about 9,7 months and RR of 60.8%. Unfortunately, all patients relapse with a median PFS of 7 to 16 months. The mechanisms of acquired resistance to first generation EGFR TKIs include a secondary EGFR mutation (T790M) in about 50% and, with less frequency, MET amplification, HER2 amplification, PTEN loss, transformation to small cell histology, EMT and rare mutations in BRAF and PI3KCA. Resistance to crizotinib is caused by ALK kinase mutations, by ALK or cKIT amplification or by alterations in IGF1R/IRS1, EGFR and KRAS. Here, we made use of next …