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EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors

Young Lim Choi1, Manabu Soda, Yoshihiro Yamashita

  • 1Division of Functional Genomics, Jichi Medical University, Tochigi, Japan.

The New England Journal of Medicine
|October 29, 2010
PubMed

Insights

Two new mutations in echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) were found in lung cancer patients resistant to ALK inhibitors. These mutations emerged independently, causing resistance to multiple targeted therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion tyrosine kinase is a key driver in 4-5% of non-small-cell lung cancers.
  • Targeted therapies inhibiting ALK are under clinical investigation for treating EML4-ALK-positive non-small-cell lung cancer.

Observation:

  • This study investigated tumor cells from a patient experiencing relapse during treatment with an ALK inhibitor.
  • Secondary mutations within the kinase domain of EML4-ALK were identified in tumor subclones.

Findings:

  • Two distinct secondary mutations in the EML4-ALK kinase domain were discovered.
  • Each mutation arose independently in separate tumor subclones.
  • These mutations conferred significant resistance to two different ALK inhibitors.

Implications:

  • The emergence of secondary mutations is a mechanism of acquired resistance to ALK inhibitors in non-small-cell lung cancer.
  • Understanding these resistance mutations is crucial for developing next-generation ALK inhibitors.
  • This highlights the importance of monitoring for resistance mechanisms during targeted cancer therapy.

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