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Detection of Targetable Alterations in Non-small Cell Lung Cancer using Next-generation Sequencing
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Detection of Targetable Alterations in Non-small Cell Lung Cancer using Next-generation Sequencing

Published on: October 10, 2025

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Alectinib shows potent antitumor activity against RET-rearranged non-small cell lung cancer

Tatsushi Kodama1, Toshiyuki Tsukaguchi1, Yasuko Satoh1

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

Molecular Cancer Therapeutics
|October 29, 2014
PubMed

Insights

Alectinib effectively inhibits RET fusion-positive cells and tumors by suppressing RET phosphorylation. This finding suggests alectinib as a potential treatment for non-small cell lung cancer (NSCLC) patients with RET fusions.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Alectinib is an anaplastic lymphoma kinase (ALK) inhibitor used for ALK fusion-positive non-small cell lung cancer (NSCLC).
  • RET and ROS1 fusion genes are emerging as key oncogenic drivers in NSCLC, presenting new therapeutic targets.
  • Understanding the broader kinase inhibitory profile of alectinib is crucial for identifying new treatment opportunities.

Purpose of the Study:

  • To investigate the potential of alectinib to inhibit kinases beyond ALK, specifically RET and ROS1.
  • To evaluate the efficacy of alectinib against RET fusion-driven cancers and its activity against specific RET mutations.

Main Methods:

  • In vitro kinase assays were performed to assess alectinib's inhibition of RET and ROS1 kinase activity.
  • Cell proliferation assays were used to evaluate the effect of alectinib on RET fusion-positive cell lines.
  • In vivo studies in mouse models were conducted to assess the antitumor activity of alectinib against RET fusion-driven tumors.
  • Kinase inhibitory activity against RET gatekeeper mutations (V804L and V804M) was evaluated.

Main Results:

  • Alectinib demonstrated significant inhibition of RET kinase activity and RET fusion-positive cell growth by suppressing RET phosphorylation.
  • Unlike other ALK/ROS1 inhibitors, alectinib showed minimal inhibition of ROS1 kinase activity.
  • Alectinib exhibited antitumor activity in mouse models of RET fusion-driven tumors.
  • Alectinib effectively inhibited RET gatekeeper mutations (V804L and V804M) and blocked cell growth driven by these mutations.

Conclusions:

  • Alectinib is effective against RET fusion-positive tumors, including those with gatekeeper mutations.
  • Alectinib shows promise as a therapeutic option for patients with RET fusion-positive non-small cell lung cancer (NSCLC).
  • The study expands the potential applications of alectinib beyond ALK-driven NSCLC.

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