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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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Early Steps of Resistance to Targeted Therapies in Non-Small-Cell Lung Cancer

Celia Delahaye1, Sarah Figarol1, Anne Pradines1,2

  • 1Cancer Research Centre of Toulouse, INSERM UMR1037, CNRS UMR5071, UPS, 31100 Toulouse, France.

Cancers
|June 10, 2022
PubMed

Insights

Drug-tolerant persister cells (DTP) in lung cancer evade EGFR-TKI therapy through reversible non-genetic changes. Understanding these mechanisms is key to developing sustainable treatments for non-small cell lung cancer (NSCLC).

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Lung cancer is a leading cause of cancer death globally.
  • Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) treat advanced non-small-cell lung cancer (NSCLC) with EGFR mutations but are not curative.
  • Resistance to EGFR-TKIs often emerges due to drug-tolerant persister cells (DTPs).

Purpose of the Study:

  • To review and discuss the molecular mechanisms underlying the drug-tolerant state in non-small-cell lung cancer.
  • To elucidate how drug-tolerant persister cells (DTPs) survive EGFR-TKI treatment.
  • To explore therapeutic strategies targeting DTPs for sustainable lung cancer treatment.

Main Methods:

  • Literature review of in vitro studies on EGFR-TKI resistance.
  • Analysis of proposed molecular mechanisms governing DTP survival.
  • Discussion of biological features and therapeutic strategies for DTPs.

Main Results:

  • Drug tolerance in NSCLC may arise from a reversible, non-genetic reprogramming of DTPs.
  • Mechanisms of DTP survival include chromatin remodeling, epigenetic changes, altered survival pathways, metabolic reprogramming, and micro-environment interactions.
  • Various therapeutic strategies targeting DTPs are under investigation.

Conclusions:

  • Understanding the dynamics of the drug-tolerant state is crucial for overcoming EGFR-TKI resistance in NSCLC.
  • Targeting DTPs offers a potential avenue for developing more effective and sustainable lung cancer therapies.
  • Further research into DTP mechanisms and targeted therapies is warranted.
Keywords:
EGFR-TKIdrug-tolerant persisterslung cancertargeted therapies

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