Activation of IGF-1R pathway and NPM-ALK G1269A mutation confer resistance to crizotinib treatment in NPM-ALK positive lymphoma

  • Yanrong Li
  • Kai Wang
  • Na Song
  • Kezuo Hou
  • Xiaofang Che
  • Yang Zhou
  • Yunpeng LiuEmail author
  • Jingdong ZhangEmail author


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.


ALK ALCL Crizotinib IGF-1R Drug resistance 



This study was supported by the National Natural Science Foundation of China (No. 81372532), and the Science and Technology Planning Project of Liaoning Province of China (No. 201800449), and the scientific research foundation for the introduction of talents, Liaoning Cancer Hospital & Institute (No. Z1702). The authors report no conflicts of interest in this work.

Compliance with ethical standards

Conflict of interests

The authors have declared that no competing interest exists.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

For this type of study, formal consent is not required.


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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Medical OncologyCancer Hospital of China Medical University, Liaoning Cancer Hospital and InstituteShenyangChina
  2. 2.Department of Medical OncologyThe First Hospital of China Medical UniversityShenyangChina
  3. 3.Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning ProvinceThe First Hospital of China Medical UniversityShenyangChina

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