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|Ref Type||Journal Article|
|Authors||Li Y, Wang K, Song N, Hou K, Che X, Zhou Y, Liu Y, Zhang J|
|Title||Activation of IGF-1R pathway and NPM-ALK G1269A mutation confer resistance to crizotinib treatment in NPM-ALK positive lymphoma.|
|Journal||Investigational new drugs|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|ASP3026||ASP-3026|ASP 3026||ALK Inhibitor 23 ROS1 Inhibitor 14||ASP3026 inhibits ALK, with activity against ALK fusions and mutations, and ROS1, potentially resulting in decreased viability of tumor cells and reduced tumor growth (PMID: 24419060, PMID: 29491259, PMID: 26964870, PMID: 31177400).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|