Mechanisms of acquired resistance to ALK inhibitors and the rationale for treating ALK-positive lung cancer

Hideko Isozaki, Nagio Takigawa, Katsuyuki Kiura

Research output: Contribution to journalArticle

45 Citations (Scopus)


The discovery of an echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene led to improved clinical outcomes in patients with lung cancer after the development of the first ALK-targeting agent, crizotinib. Some second-generation ALK tyrosine kinase inhibitors (TKIs), which might be more potent than crizotinib or effective on crizotinib-resistant patients, have been developed. Although these ALK-TKIs show an excellent response initially, most patients eventually acquire resistance. Therefore, careful consideration of the resistance mechanisms might lead to superior therapeutic strategies. Here, we summarize the history of ALK-TKIs and their underlying resistance mechanisms in both the preclinical and clinical settings. In addition, we discuss potential future treatment strategies in ALK-TKI-naïve and -resistant patients with lung cancer harboring the EML4-ALK fusion gene.

Original languageEnglish
Pages (from-to)763-783
Number of pages21
Issue number2
Publication statusPublished - Apr 30 2015



  • Alectinib
  • Ceritinib
  • Crizotinib
  • EML4-ALK
  • Lung cancer
  • Resistance

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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