二代ALK抑制剂耐药的原因与治疗,与癌共舞,前沿信息

http://www.ncbi.nlm./pubmed/26992917Neoplasia. 2016 Mar;18(3):162-71. doi: 10.1016/j.neo.2016.02.001.

Elucidation of Resistance Mechanisms to Second-Generation ALK Inhibitors Alectinib and Ceritinib in Non-Small Cell Lung Cancer Cells.

文中指出二代ALK抑制剂Alectinib 和 Ceritinib 耐药是由 以 NRG1-HER3-EGFR 为主线的信号通路所致，使用二代泛EGFR抑制剂阿法替尼（pf2992）可治疗二代ALK抑制剂耐药。Dong X1, Fernandez-Salas E2, Li E3, Wang S4.

Author information

• 1Department of Medical Oncology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P.R. China; University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
• 2University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
• 3Department of Medical Oncology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P.R. China. Electronic address: [e-mail].
• 4University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, 48109, USA; Department of Pharmacology, University of Michigan, Ann Arbor, MI, 48109, USA; Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, 48109, USA. Electronic address: [e-mail].
  
  

AbstractCrizotinib is the first anaplastic lymphoma kinase (ALK) inhibitor to have been approved for the treatment of non-small cell lung cancer (NSCLC) harboring an ALK fusion gene, but it has been found that, in the clinic, patients develop resistance to it. Alectinib and ceritinib are second-generation ALK inhibitors which show remarkable clinical responses in both crizotinib-naive and crizotinib-resistant NSCLC patients harboring an ALK fusion gene. Despite their impressive activity, clinical resistance to alectinib and ceritinib has also emerged. In the current study, we elucidated the resistance mechanisms to these second-generation ALK inhibitors in the H3122 NSCLC cell line harboring the EML4-ALK variant 1 fusion in vitro. Prolonged treatment of the parental H3122 cells with alectinib and ceritinib led to two cell lines which are 10 times less sensitive to alectinib and ceritinib than the parental H3122 cell line. Although mutations of ALK in its kinase domain are a common resistance mechanism for crizotinib, we did not detect any ALK mutation in these resistant cell lines. Rather, overexpression of phospho-ALK and alternative receptor tyrosine kinases such as phospho-EGFR, phospho-HER3, and phospho-IGFR-1R was observed in both resistant cell lines. Additionally, NRG1, a ligand for HER3, is upregulated and responsible for resistance by activating the EGFR family pathways through the NRG1-HER3-EGFR axis. Combination treatment with EGFR inhibitors, in particular afatinib, was shown to be effective at overcoming resistance. Our study provides new mechanistic insights into adaptive resistance to second-generation ALK inhibitors and suggests a potential clinical strategy to combat resistance to these second-generation ALK inhibitors in NSCLC.

Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.