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Detection of Targetable Alterations in Non-small Cell Lung Cancer using Next-generation Sequencing
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Identification of Genomic Alterations Acquired During Treatment With EGFR-TKIs in Non-small Cell Lung Cancer

Naoki Kubo1,2, Taishi Harada3,4, Yoshimasa Shiraishi1,5

  • 1Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Anticancer Research
|February 4, 2019
PubMed
Abstract

Insights

Acquired genomic alterations drive resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). Understanding these changes, like T790M mutations and MET amplification, is key to overcoming treatment resistance.

Area of Science:

  • Oncology
  • Genomics
  • Molecular Biology

Background:

  • Non-small cell lung cancer (NSCLC) patients treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) often develop drug resistance.
  • The precise mechanisms underlying EGFR-TKI resistance remain incompletely understood in many cases.

Purpose of the Study:

  • To investigate the genomic landscape of acquired resistance to EGFR tyrosine kinase inhibitors in non-small cell lung cancer.
  • To identify novel genomic alterations associated with the development of EGFR-TKI resistance.

Main Methods:

  • Whole-exome sequencing was performed on tumor tissue from 15 NSCLC patients who developed acquired resistance to EGFR-TKIs.
  • Genomic alterations occurring during treatment were analyzed by comparing pre-treatment tumor samples (n=4) and normal white blood cell samples (n=6) with post-treatment tumor tissues.

Main Results:

  • Significant inter-patient variability was observed in mutational signatures and mutational load acquired during EGFR-TKI treatment.
  • Common resistance mechanisms identified include the T790M secondary mutation in EGFR and MET amplification.
  • Numerous other genomic alterations were acquired concurrently with known resistance mechanisms, highlighting a complex mutational landscape.

Conclusions:

  • The development of EGFR-TKI resistance in NSCLC is characterized by a diverse array of acquired genomic alterations.
  • Identifying these acquired mutations and amplifications provides crucial insights into resistance mechanisms.
  • Further research into these genomic changes may lead to strategies to overcome or prevent EGFR-TKI resistance in NSCLC.
Keywords:
EGFR-TKINon-small cell lung cancerdrug resistanceexome sequencinggenomic mutation

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