Résumé
Lung cancer is by far the major cause of cancer-related death. The identification of oncogenic mutations in the genes encoding for the epidermal growth factor receptor (EGFR) and the anaplastic lymphoma kinase (ALK) opened the way for development of relatively effective tyrosine kinase inhibitory (TKI) drugs, such as erlotinib and crizotinib, respectively. Unfortunately, resistance to these and other first-generation TKIs evolves in patients within a year or two. Several mechanisms underlie acquired resistance and they include second-site mutations, compensatory signaling pathways and phenotype alterations. Once resolved, mechanisms conferring resistance to TKIs may pave the way for next-generation TKIs, or they may identify combination therapies simultaneously inhibiting the primary and alternative routes to oncogenesis. Herein, we review the first-, second- and third-generation inhibitors of EGFR and ALK, along with the many ways permitting lung cancer cells to evade pharmacological interceptors in experimental systems and in clinical settings.