The EGFR T790M mutation in acquired resistance to an irreversible second-generation EGFR inhibitor
Menée in vitro, cette étude identifie un mécanisme de résistance aux molécules de la deuxième génération d'inhibiteurs de tyrosine kinase dans le cancer du poumon non à petites cellules
Molecular target therapies using the first-generation reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib or erlotinib, have been shown to be effective for non-small cell lung cancer (NSCLC) patients who harbor activating mutations in EGFR. However, these patients eventually develop resistance to the reversible TKIs, and this has led to the development of second-generation irreversible EGFR inhibitors. Currently, the mechanism of acquired resistance to irreversible EGFR inhibitors is not clear. Using an in vitro cell culture system, we modeled the acquired resistance to first-line treatment with second-generation EGFR-TKIs, using an EGFR mutant NSCLC cell line. Here we report a mechanism of resistance involving T790M secondary mutation as well as a corresponding clinical case. The results of these findings suggest that inhibition of EGFR by currently available second-generation EGFR-TKIs may not be sufficient to physiologically prevent the emergence of cells that are still dependent on EGFR signaling. This finding bears important implications on the limitations of currently available second-generation EGFR TKIs.
http://mct.aacrjournals.org/content/early/2012/01/06/1535-7163.MCT-11-0750.abstract