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Sequential ALK Inhibitors Can Select for Lorlatinib-Resistant Compound ALK Mutations in ALK-Positive Lung Cancer

Satoshi Yoda1,2, Jessica J Lin1,2, Michael S Lawrence1,2,3

  • 1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.

Cancer Discovery
|April 14, 2018
PubMed

Insights

Sequential ALK inhibitors for lung cancer can lead to compound ALK mutations, causing resistance. Early use of third-generation inhibitors like lorlatinib may prevent this resistance by avoiding stepwise mutation accumulation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Advanced anaplastic lymphoma kinase (ALK)-positive lung cancer treatment relies on sequential ALK inhibitors.
  • Lorlatinib, a third-generation ALK inhibitor, shows activity in patients resistant to prior inhibitors.
  • Understanding ALK mutations conferring lorlatinib resistance is crucial for optimizing therapy.

Purpose of the Study:

  • To identify the spectrum of ALK mutations that cause resistance to lorlatinib.
  • To assess the clinical relevance of compound ALK mutations in patients treated with sequential ALK inhibitors.

Main Methods:

  • Accelerated mutagenesis screening of Ba/F3 cells expressing EML4-ALK using N-ethyl-N-nitrosourea (ENU).
  • Analysis of repeat tumor biopsies from patients who developed resistance to lorlatinib.
  • Whole-exome sequencing to confirm stepwise accumulation of ALK mutations.

Main Results:

  • ENU mutagenesis generated crizotinib-resistant single ALK mutations but no lorlatinib-resistant single mutations.
  • Compound ALK mutations conferring lorlatinib resistance were generated in screens with pre-existing single mutations.
  • 35% of lorlatinib-resistant patient samples harbored compound ALK mutations, with some identified in mutagenesis screens.
  • Whole-exome sequencing confirmed stepwise ALK mutation acquisition during sequential treatment.

Conclusions:

  • Sequential ALK inhibitor therapy can drive the emergence of compound ALK mutations, leading to high-level resistance.
  • Identifying these compound mutations is vital for developing new drugs and treatment strategies.
  • Up-front treatment with a third-generation ALK inhibitor may be a more effective long-term strategy to prevent on-target resistance.

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