Molecular Mechanisms of Resistance to First- And Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer

Cancer Discov. 2016 Oct;6(10):1118-1133. doi: 10.1158/2159-8290.CD-16-0596. Epub 2016 Jul 18.

Abstract

Advanced, anaplastic lymphoma kinase (ALK)-positive lung cancer is currently treated with the first-generation ALK inhibitor crizotinib followed by more potent, second-generation ALK inhibitors (e.g., ceritinib and alectinib) upon progression. Second-generation inhibitors are generally effective even in the absence of crizotinib-resistant ALK mutations, likely reflecting incomplete inhibition of ALK by crizotinib in many cases. Herein, we analyzed 103 repeat biopsies from ALK-positive patients progressing on various ALK inhibitors. We find that each ALK inhibitor is associated with a distinct spectrum of ALK resistance mutations and that the frequency of one mutation, ALKG1202R, increases significantly after treatment with second-generation agents. To investigate strategies to overcome resistance to second-generation ALK inhibitors, we examine the activity of the third-generation ALK inhibitor lorlatinib in a series of ceritinib-resistant, patient-derived cell lines, and observe that the presence of ALK resistance mutations is highly predictive for sensitivity to lorlatinib, whereas those cell lines without ALK mutations are resistant.

Significance: Secondary ALK mutations are a common resistance mechanism to second-generation ALK inhibitors and predict for sensitivity to the third-generation ALK inhibitor lorlatinib. These findings highlight the importance of repeat biopsies and genotyping following disease progression on targeted therapies, particularly second-generation ALK inhibitors. Cancer Discov; 6(10); 1118-33. ©2016 AACRSee related commentary by Qiao and Lovly, p. 1084This article is highlighted in the In This Issue feature, p. 1069.

MeSH terms

  • Anaplastic Lymphoma Kinase
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Drug Resistance, Neoplasm* / drug effects
  • Humans
  • Lactams, Macrocyclic / pharmacology*
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics*
  • Mutation
  • Protein Kinase Inhibitors / pharmacology
  • Pyrimidines / pharmacology
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Sulfones / pharmacology

Substances

  • Lactams, Macrocyclic
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Sulfones
  • ALK protein, human
  • Anaplastic Lymphoma Kinase
  • Receptor Protein-Tyrosine Kinases
  • ceritinib
  • lorlatinib