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Endothelin-1-Mediated Drug Resistance in EGFR-Mutant Non-Small Cell Lung Carcinoma

Inés Pulido1,2,3, Stephen Ollosi4, Salvador Aparisi3

  • 1Department of Surgery, Division of Cardiothoracic Surgery, University of Illinois at Chicago, Chicago, Illinois.

Cancer Research
|August 5, 2020
PubMed

Insights

In EGFR-mutant non-small cell lung cancer, endothelin-1 (EDN1) limits drug delivery by causing vasoconstriction. Blocking EDN1 or its receptor can improve drug penetration and overcome resistance.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Radiographic evaluation of non-small cell lung cancer (NSCLC) therapy may not differentiate drug resistance from poor drug delivery.
  • Mutated EGFR (epidermal growth factor receptor) inhibition in NSCLC can promote endothelin-1 (EDN1) secretion, a vasoconstrictor linked to cancer progression.
  • Endothelin receptor (EDNR) antagonists have shown disappointing results in clinical trials, as trials did not assess EDN1's role in tumor microenvironment modification or drug resistance.

Purpose of the Study:

  • To investigate the role of tumor-derived endothelin-1 (EDN1) in mediating drug resistance in EGFR-mutant non-small cell lung cancer (NSCLC).
  • To evaluate the potential of repurposing EDNR antagonists to improve drug delivery and overcome resistance in NSCLC.

Main Methods:

  • Ectopic overexpression of EDN1 in EGFR-mutant NSCLC cells to assess effects on drug delivery and tumor growth in vitro and in vivo.
  • Intratumoral injection of recombinant EDN in xenografted EGFR-mutant tumors to evaluate impact on blood flow and drug accumulation.
  • Assessment of drug penetration and tumor blood flow following EDN1 depletion or treatment with EDNR inhibitors (bosentan, ambrisentan).

Main Results:

  • Ectopic EDN1 overexpression resulted in poor drug delivery and retarded tumor growth in vivo, but not in vitro.
  • Intratumoral EDN administration significantly reduced tumor blood flow and gefitinib accumulation in EGFR-mutant xenografts.
  • EDN1 depletion or EDNR inhibition improved drug penetration, restored tumor vasculature blood flow, and potentially overcame resistance.

Conclusions:

  • A previously unrecognized resistance mechanism in EGFR-mutant NSCLC involves EDN1-mediated vasoconstriction, limiting tyrosine kinase inhibitor (TKI) delivery.
  • EDNR antagonists represent a viable strategy for repurposing to enhance drug delivery in specific NSCLC tumors, particularly those secreting EDN1 in response to TKI treatment.
  • Targeting the EDN1-EDNR axis can improve therapeutic efficacy by optimizing drug delivery to the tumor microenvironment.

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