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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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AKT inactivation causes persistent drug tolerance to EGFR inhibitors

Osamu Tetsu1, Janyaporn Phuchareon1, David W Eisele1

  • 1Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of California, San Francisco, CA, USA; UCSF Helen Diller Family Comprehensive Cancer Center, School of Medicine, University of California, San Francisco, CA, USA.

Pharmacological Research
|October 11, 2015
PubMed

Insights

Drug resistance in EGFR-mutant lung cancer arises from EGFR inhibition inactivating AKT and Ets-1. Combined TKI and MEK inhibitor treatment may overcome this emergent resistance in non-small cell lung cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Drug resistance is a significant challenge in EGFR-targeted cancer therapy.
  • A subset of EGFR-mutant lung cancer cells survives EGFR inhibition.
  • Understanding the mechanisms of this drug tolerance is crucial for improving treatment outcomes.

Purpose of the Study:

  • To investigate the mechanism of drug resistance in EGFR-mutant lung cancer cells following EGFR inhibition.
  • To identify key signaling pathways involved in the development of drug tolerance.
  • To propose therapeutic strategies to overcome emergent resistance to EGFR TKIs.

Main Methods:

  • Analysis of cell signaling pathways in EGFR-mutant lung cancer cells after EGFR inhibition.
  • Investigating the role of AKT and Ets-1 in drug tolerance.
  • Evaluating the efficacy of combined TKI and MEK inhibitor treatment.

Main Results:

  • EGFR inhibition leads to decreased AKT activity, subsequently inactivating Ets-1 function.
  • This inactivation of Ets-1 contributes to the survival of a drug-tolerant subpopulation.
  • Changes in intrinsic cell signaling pathways mediate emergent drug resistance in NSCLCs.

Conclusions:

  • EGFR inhibition triggers a signaling cascade leading to drug resistance in non-small cell lung cancers (NSCLCs).
  • Targeting the AKT-Ets-1 pathway is a potential strategy to combat resistance.
  • Combined treatment with EGFR TKIs and MEK inhibitors may reduce the incidence of emergent resistance.
Keywords:
AKT protein kinaseBcl-2 interacting protein BimDrug resistanceDrug tolerant persister cellsDual specificity phosphatase 6 (DUSP6)ERK1/2 paradoxical activationEpidermal growth factor receptor (EGFR) inhibitionErlotinib (Tarceva)Ets-1 transcription factorGefitinib (Iressa)Lapatinib (Tykerb)Non-small-cell lung cancer (NSCLC)PD325901Saracatinib (AZD0530)Tyrosine kinase inhibitors (TKIs)

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