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MUC1-C Is a Common Driver of Acquired Osimertinib Resistance in NSCLC

Naoki Haratake1, Hiroki Ozawa1, Yoshihiro Morimoto1

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute Harvard Medical School, Boston, Massachusetts.

Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer
|November 4, 2023
PubMed
Abstract

Insights

MUC1-C is a key driver of osimertinib resistance in non-small cell lung cancer (NSCLC). Targeting MUC1-C can reverse resistance and offers a new therapeutic strategy for patients with EGFR-mutant NSCLC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Resistance

Background:

  • Osimertinib is a first-line treatment for metastatic non-small cell lung cancer (NSCLC) with specific EGFR mutations.
  • Acquired resistance to osimertinib develops through various mechanisms, including EGFR mutations and MET amplification.
  • The role of the oncogenic MUC1-C protein in osimertinib resistance was previously unknown.

Purpose of the Study:

  • To investigate the dependence of osimertinib-resistant NSCLC cells on MUC1-C.
  • To determine if MUC1-C is a common mechanism underlying acquired osimertinib resistance.
  • To evaluate MUC1-C as a potential therapeutic target for overcoming osimertinib resistance.

Main Methods:

  • Investigated MUC1-C dependence in NSCLC cell lines with acquired osimertinib resistance (H1975-OR, MGH700-2D, MGH170-1D #2, MGH121 Res#2).
  • Assessed EGFR pathway activation (p-EGFR, p-ERK, p-AKT), epithelial-mesenchymal transition (EMT), clonogenicity, and self-renewal capacity.
  • Examined the effect of targeting MUC1-C on osimertinib resistance in vitro.

Main Results:

  • MUC1-C is upregulated in osimertinib-resistant NSCLC cells and is essential for EGFR pathway activation.
  • MUC1-C is required for maintaining the resistant phenotype, EMT, and self-renewal capacity in diverse resistant models.
  • Targeting MUC1-C effectively reversed osimertinib resistance across multiple resistant NSCLC models.
  • High MUC1 expression correlates with poor prognosis in EGFR-mutant NSCLC patients.

Conclusions:

  • MUC1-C is a common and critical mediator of acquired osimertinib resistance in NSCLC.
  • MUC1-C represents a promising therapeutic target for treating patients with osimertinib-resistant NSCLC.
  • Targeting MUC1-C offers a potential strategy to overcome resistance and improve outcomes for NSCLC patients.
Keywords:
EGFRMUC1-CNSCLCOsimertinibResistance

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