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Selective ALK inhibitor alectinib with potent antitumor activity in models of crizotinib resistance

Tatsushi Kodama1, Toshiyuki Tsukaguchi1, Miyuki Yoshida1

  • 1Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan.

Cancer Letters
|June 3, 2014
PubMed

Insights

Alectinib shows efficacy against Anaplastic Lymphoma Kinase (ALK) secondary mutations that cause resistance to crizotinib in non-small cell lung cancer (NSCLC). This suggests alectinib may benefit patients resistant to prior ALK inhibitor therapy.

Area of Science:

  • Oncology
  • Pharmacology
  • Genetics

Background:

  • Crizotinib is an effective Anaplastic Lymphoma Kinase (ALK) inhibitor for ALK fusion-positive non-small cell lung cancer (NSCLC).
  • Secondary mutations in ALK are a common mechanism of acquired resistance to crizotinib during clinical treatment.

Purpose of the Study:

  • To evaluate the efficacy of alectinib, a selective ALK inhibitor, in preclinical models of crizotinib resistance.
  • To determine if alectinib can overcome resistance mediated by ALK secondary mutations.

Main Methods:

  • Utilized xenograft tumor models of EML4-ALK-positive non-small cell lung cancer.
  • Assessed tumor response to crizotinib and subsequent treatment with alectinib.
  • Investigated the activity of alectinib against specific EML4-ALK mutations, including G1269A.

Main Results:

  • Alectinib demonstrated tumor size reduction in EML4-ALK-positive xenografts that were resistant to crizotinib.
  • Alectinib effectively inhibited the growth of tumors driven by certain EML4-ALK mutations, such as G1269A.
  • The study confirmed alectinib's activity against models with ALK secondary mutations conferring crizotinib resistance.

Conclusions:

  • Alectinib exhibits potent anti-tumor activity in models of crizotinib resistance driven by ALK secondary mutations.
  • Alectinib represents a potential therapeutic option for non-small cell lung cancer patients who have developed resistance to crizotinib.
  • These findings support the clinical investigation of alectinib in patients with ALK-mutated NSCLC progressing on crizotinib.
Keywords:
ALKALK inhibitorAlectinibDrug resistanceNSCLCXenograft model

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