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Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
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Upregulation of Bcl2 in NSCLC with acquired resistance to EGFR-TKI

Hio Teng Cheong1, Fei Xu2, Chi Tung Choy1

  • 1Department of Clinical Oncology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, SAR, P.R. China.

Oncology Letters
|February 10, 2018
PubMed

Insights

Non-small cell lung cancer (NSCLC) patients develop resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Targeting B-cell lymphoma 2 (Bcl2) may overcome this resistance, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide, with 80% of cases being NSCLC.
  • Resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is a significant clinical challenge, typically developing within 8-12 months of treatment.
  • Understanding the mechanisms of acquired resistance is crucial for developing effective treatment strategies.

Purpose of the Study:

  • To investigate the mechanisms underlying acquired resistance to EGFR-TKIs in NSCLC.
  • To identify potential therapeutic targets to overcome EGFR-TKI resistance.

Main Methods:

  • Screening and characterization of HCC827 cell lines exhibiting resistance to EGFR-TKIs.
  • Quantification of half maximal inhibitory concentration (IC50) values to assess drug resistance.
  • Analysis of B-cell lymphoma 2 (Bcl2) expression in resistant cell lines and patient biopsies.
  • Investigation of the phosphatase and tensin homolog (PTEN)/phosphoinositide 3-kinase (PI3K) signaling axis.

Main Results:

  • Resistant HCC827 cell lines demonstrated a 1,000-fold increase in IC50 values compared to parental cells, indicating significant cross-resistance to TKIs.
  • Markedly increased expression of B-cell lymphoma 2 (Bcl2) was observed in resistant clones and patient biopsies.
  • The PTEN/PI3K signaling axis was implicated as a potential mechanism contributing to acquired resistance.

Conclusions:

  • Acquired resistance to EGFR-TKIs in NSCLC is associated with increased Bcl2 expression.
  • The PTEN/PI3K pathway may play a role in the development of this resistance.
  • Targeting Bcl2 represents a promising therapeutic strategy for overcoming EGFR-TKI resistance in NSCLC patients.
Keywords:
B-cell lymphoma 2acquired resistanceepidermal growth factor receptor-tyrosine kinase inhibitornon-small cell lung cancer

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