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Updated: Mar 13, 2026

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
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The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK

Sen Zhang1, Rana Anjum1, Rachel Squillace1

  • 1ARIAD Pharmaceuticals, Inc, Cambridge, Massachusetts.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|November 1, 2016
PubMed
Abstract

Insights

Brigatinib is a potent and selective next-generation ALK inhibitor that shows superior efficacy against ALK-positive non-small cell lung cancer, including resistant mutations. This offers a promising new treatment option for patients resistant to earlier therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Non-small cell lung cancer (NSCLC) with ALK gene rearrangements (ALK+) often develops resistance to crizotinib, a first-generation ALK tyrosine kinase inhibitor (TKI).
  • Secondary mutations in ALK and brain metastases are common mechanisms of resistance to existing ALK TKIs.
  • There is a need for next-generation ALK TKIs effective against resistant mutations and brain disease.

Purpose of the Study:

  • To conduct the first comprehensive preclinical evaluation of brigatinib, a next-generation ALK TKI.
  • To assess the structure, selectivity, and in vitro and in vivo activity of brigatinib.
  • To compare brigatinib's efficacy against ALK-resistant mutations relative to other ALK TKIs.

Main Methods:

  • Kinase screening was performed to determine brigatinib's selectivity profile.
  • Cellular and in vivo assays were used to compare the activities of brigatinib and other ALK TKIs.
  • The co-structure of brigatinib bound to ALK was determined.

Main Results:

  • Brigatinib demonstrated potent inhibition of ALK and ROS1 with high selectivity (>250 kinases).
  • Brigatinib showed 12-fold greater potency than crizotinib against ALK+ cell lines and superior efficacy in preclinical models, including brain metastases.
  • Brigatinib maintained activity against all tested ALK resistance mutations, including the G1202R mutation, outperforming crizotinib, ceritinib, and alectinib.

Conclusions:

  • Brigatinib is a highly potent and selective ALK inhibitor with broad activity against ALK mutations.
  • Structural analyses support brigatinib's unique inhibitory profile against resistant ALK mutants.
  • These preclinical findings provide a strong rationale for the clinical activity observed in ALK+ NSCLC patients resistant to crizotinib.

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