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Updated: Jan 5, 2026

Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
11:15

Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors

Published on: September 20, 2016

24.9K

TKI-resistant ALK-rearranged lung adenocarcinoma with secondary CTNNB1 p.S45V and tertiary ALK p.I1171N mutations

Madhu M Ouseph1, Angela Taber2, Humera Khurshid3

  • 1Department of Pathology, Rhode Island Hospital and Alpert Medical School at Brown University, Providence, RI 02903, USA.

Lung Cancer (Auckland, N.Z.)
|October 17, 2019
PubMed

Insights

Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) can develop resistance to targeted therapies. Genomic profiling revealed new mutations, including CTNNB1 and ALK, driving resistance and suggesting new treatment avenues.

Area of Science:

  • Oncology
  • Genomics
  • Molecular Biology

Background:

  • Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) is a distinct molecular subtype.
  • While initially responsive to tyrosine kinase inhibitors (TKIs), acquired resistance limits long-term efficacy.
  • Understanding resistance mechanisms is crucial for improving patient outcomes.

Purpose of the Study:

  • To investigate the genomic evolution and resistance mechanisms in a patient with ALK-rearranged NSCLC treated with multiple TKIs.
  • To identify secondary and tertiary mutations contributing to therapeutic resistance.

Main Methods:

  • Serial comprehensive genomic profiling (CGP) of tumor samples.
  • Analysis of clonal progression and mutation acquisition during TKI treatment.

Main Results:

  • Initial response to targeted therapy followed by acquired resistance.
  • CGP identified a secondary CTNNB1 p.S45V mutation and a tertiary ALK p.I1171N mutation.
  • These alterations suggest novel resistance pathways and potential therapeutic targets.

Conclusions:

  • Tumor progression in ALK-rearranged NSCLC can be driven by secondary oncogenic driver mutations.
  • Genomic profiling is essential for understanding resistance and guiding subsequent treatment strategies.
  • Targeting Wnt signaling, influenced by CTNNB1 mutations, may offer new therapeutic avenues.
Keywords:
beta-catenincancergenomicsprofilingresistance

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