Mechanisms of acquired resistance to epidermal growth factor receptor XXXX kinase inhibitors and new therapeutic perspectives in non small cell lung cancer.

@entity1 @entity470 @entity5 @entity319 @entity669
@entity470 somatic mutations define a subset of NSCLCs that are most likely to benefit from @entity470 @entity669 kinase inhibitors (TKIs). These @entity5 are dependent on @entity470 -signaling for survival. Recently, @entity669 kinase domain somatic mutations have been approved as criterion to decide first-line therapy in this group of advanced NSCLCs. Anyway, all @entity1 ultimately develop resistance to these drugs. Acquired resistance is linked to a secondary @entity470 mutation in about a half of @entity1 . Uncontrolled activation of MET, another @entity669 kinase receptor, has been implicated in neoplastic invasive growth. MET is overexpressed, activated and sometimes mutated in NSCLC cell lines and @entity5 tissues. MET increased gene copy number has also been documented in NSCLC and has been studied as negative prognostic factor. It has also been found in about 20% of @entity1 developing acquired resistance to TKIs inhibitors. In this group, it seems to display a new mechanism, which is able to mark @entity5 independence from @entity470 signaling. The study of delayed resistance mechanisms could lead to the development of new therapeutic strategies. Different molecular alterations could be specifically targeted in order to extend disease control in this group of NSCLCs with distinct clinical and molecular features. @entity470 irreversible inhibitors, MET inhibitors and dual @entity470 / @entity319 inhibitors represent one of the most challenging issues in current clinical research. Ongoing clinical trials and future perspectives are discussed.
