ALK Mutations Conferring Differential Resistance to Structurally Diverse ALK Inhibitors

摘要: Purpose: EML4 – ALK fusions define a subset of lung cancers that can be effectively treated with anaplastic lymphoma kinase (ALK) inhibitors. Unfortunately, the duration response is heterogeneous and acquired resistance limits their ultimate efficacy. Thus, better understanding mechanisms will help to enhance tumor control in -positive tumors. Experimental Design: By applying orthogonal functional mutagenesis screening approaches, we screened for mutations inducing aminopyridine PF02341066 (crizotinib) and/or diaminopyrimidine TAE684. Results: Here, show mutation, L1196M, as well other crizotinib (F1174L G1269S), are highly sensitive structurally unrelated inhibitor In addition, identified two novel (L1198P D1203N), which unlike previously reported mutations, induced both An independent screen -mutant neuroblastoma cells yielded same L1198P mutation but defined additional conferring TAE684 not PF02341066. Conclusions: Our results different inhibitors impact therapeutic efficacy setting mutations. Clin Cancer Res; 17(23); 7394–401. ©2011 AACR .