Crizotinib-resistant mutants of EML4-ALK identified through an accelerated mutagenesis screen.

摘要: Activating gene rearrangements of anaplastic lymphoma kinase (ALK) have been identified as driver mutations in non-small-cell lung cancer, inflammatory myofibroblastic tumors, and other cancers. Crizotinib, a dual MET/ALK inhibitor, has demonstrated promising clinical activity patients with cancer tumors harboring ALK translocations. Inhibitors kinases often elicit domain that confer resistance, such successfully predicted using vitro mutagenesis screens. Here, this approach was used to discover an extensive set can resistance crizotinib. Mutations at 16 residues were identified, structurally clustered into five regions around the active site, which conferred varying degrees resistance. The screen L1196M, C1156Y, F1174L mutations, recently crizotinib-resistant patients. In separate studies, we crizotinib relatively modest potency ALK-positive cell lines. A more potent TAE684, maintained substantial against Our study identifies multiple novel may crizotinib, suggests crizotinib's narrow selectivity window underlie its susceptibility demonstrates inhibitor be effective overcoming