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CD44s and CD44v8-10 isoforms confer acquired resistance to osimertinib by activating the ErbB3/STAT3 signaling

Yi-Nan Liu1, Meng-Feng Tsai2, Shang-Gin Wu3

  • 1Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.

Life Sciences
|December 13, 2023
PubMed
Abstract

Insights

CD44 splicing variants drive acquired resistance to osimertinib in lung cancer by co-opting the ErbB3 signaling pathway. Targeting CD44/ErbB3 signaling offers a potential strategy to overcome this resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Epidermal growth factor receptor (EGFR)-mutant lung cancers initially respond to osimertinib.
  • Acquired resistance to osimertinib, both EGFR-dependent and independent, poses a significant clinical challenge.
  • CD44 splicing variants are prevalent in lung cancer, but their role in osimertinib resistance is not well understood.

Purpose of the Study:

  • To investigate the involvement of CD44 splicing variants in acquired resistance to osimertinib in lung cancer.
  • To elucidate the molecular mechanisms by which CD44 variants contribute to osimertinib resistance.
  • To explore CD44/ErbB3 signaling as a potential therapeutic target.

Main Methods:

  • Real-time PCR to quantify CD44 and its splicing variants (CD44s, CD44v).
  • Gene knockdown and restoration experiments to assess the impact of CD44 variants on osimertinib sensitivity.
  • Analysis of signaling pathways using receptor-tyrosine-kinase phosphorylation arrays, co-immunoprecipitation, and western blotting.

Main Results:

  • Total CD44 expression increased in lung adenocarcinomas with acquired osimertinib resistance.
  • Osimertinib-resistant cells exhibited elevated levels of CD44s or CD44v variants.
  • CD44 knockdown sensitized resistant cells to osimertinib, while CD44s or CD44v8-10 restoration induced resistance.
  • CD44 was found to interact with and transactivate ErbB3, activating the ErbB3/STAT3 pathway.

Conclusions:

  • CD44 acts as a co-receptor for ErbB3, activating the ErbB3 signaling axis and mediating acquired osimertinib resistance.
  • The CD44/ErbB3 signaling pathway is a critical mechanism underlying osimertinib resistance in lung cancer.
  • Targeting CD44/ErbB3 signaling presents a promising therapeutic strategy to overcome osimertinib resistance.
Keywords:
Acquired resistanceCD44 isoformLung cancerOsimertinib

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