期刊
INVESTIGATIONAL NEW DRUGS
卷 38, 期 3, 页码 599-609出版社
SPRINGER
DOI: 10.1007/s10637-019-00802-7
关键词
ALK; ALCL; Crizotinib; IGF-1R; Drug resistance
ALK-positive anaplastic large cell lymphoma (ALCL) represents a subset of non-Hodgkin's lymphoma that is treated with crizotinib, a dual ALK/MET inhibitor. Despite the remarkable initial response, ALCLs eventually develop resistance to crizotinib. ALK inhibitor resistance in tumors is a complex and heterogeneous process with multiple underlying mechanisms, including ALK gene amplification, ALK kinase domain mutation, and the activation of various bypass signaling pathways. To overcome resistance, multiple promising next-generation ALK kinase inhibitors and rational combinatorial strategies are being developed. To determine how cancers acquire resistance to ALK inhibitors, we established a model of acquired crizotinib resistance by exposing a highly sensitive NPM-ALK-positive ALCL cell line to increasing doses of crizotinib until resistance emerged. We found that the NPM-ALK mutation was selected under intermediate-concentration drug stress in resistant clones, accompanied by activation of the IGF-1R pathway. In the crizotinib-resistant ALCL cell model, the IGF-1R pathway was activated, and combined ALK/IGF-1R inhibition improved therapeutic efficacy. Furthermore, we also detected the NPM-ALK G1269A mutation, which had previously been demonstrated to result in decreased affinity for crizotinib, in the resistant cell model. Although crizotinib was ineffective against cells harboring the NPM-ALK G1269A mutation, five structurally different ALK inhibitors, alectinib, ceritinib, TAE684, ASP3026 and AP26113, maintained activity against the resistant cells. Thus, we have shown that second-generation ALK tyrosine kinase inhibitors or IGF-1R inhibitors are effective in treating crizotinib-resistant tumors.
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