Reference Detail

Ref Type

Journal Article

PMID

(31177400)

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	Vol	Issue	Date	Pages	Journal Short Title
Investigational new drugs	38	3	2020 Jun	599-609	Invest New Drugs

URL

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
ASP3026	ASP3026	16	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
ASP3026		ASP-3026\|ASP 3026	ALK Inhibitor 32 ROS1 Inhibitor 20	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