The mechanisms of resistance to second- and third-generation ALK inhibitors and strategies to overcome such resistance

Naoki Haratake, Gouji Toyokawa, Takashi Seto, Tetsuzo Tagawa, Tasuro Okamoto, Koji Yamazaki, Sadanori Takeo, Masaki Mori

Research output: Contribution to journalReview articlepeer-review

Abstract

Introduction: Anaplastic lymphoma kinase (ALK) inhibitors are widely known to contribute to the long-term survival of ALK-rearranged non-small cell lung cancer (NSCLC) patients. Based on clinical trial data, treatment with second- or third-generation ALK inhibitors can be initiated after crizotinib therapy without analyzing resistance mechanisms, and some randomized trials have recently shown the superiority of second- or third-generation ALK inhibitors over crizotinib as the initial treatment; however, the optimal treatment for patients who relapse while on second- or third-generation ALK inhibitors is not well-defined. Areas covered: This review provides an overview of the mechanisms of resistance to second- or third-generation ALK inhibitors that have been identified in both clinical and pre-clinical settings, and introduces strategies for overcoming resistance and discusses ongoing clinical trials. Expert opinion: The comprehensive elucidation of both ALK-dependent and ALK-independent resistance mechanisms is necessary to improve the prognosis of patients with ALK-rearranged NSCLC. Liquid biopsy to clarify these mechanisms of resistance might play an important role in the near future.

Original languageEnglish
Pages (from-to)975-988
Number of pages14
JournalExpert Review of Anticancer Therapy
Volume21
Issue number9
DOIs
Publication statusPublished - 2021

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pharmacology (medical)

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