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Elevated RET expression enhances EGFR activation and mediates EGFR inhibitor resistance in head and neck squamous

Chengzhong Lin1, Wei Lu1, Zhenhu Ren1

  • 1Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China; Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, Shanghai 200011, China.

Cancer Letters
|April 20, 2016
PubMed
Abstract

Insights

Targeting rearranged during transfection (RET) signaling improves EGFR inhibitor efficacy in head and neck squamous cell carcinoma (HNSCC). This study demonstrates RET inhibition as a viable strategy to overcome resistance to erlotinib in HNSCC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Resistance to Epidermal Growth Factor Receptor (EGFR) inhibitors like erlotinib is a challenge in head and neck squamous cell carcinoma (HNSCC).
  • Alternative receptor tyrosine kinases (RTKs) co-activation is a suspected mechanism for EGFR inhibitor resistance.

Purpose of the Study:

  • To investigate the role of rearranged during transfection (RET) signaling in HNSCC.
  • To determine if targeting RET can enhance the efficacy of EGFR inhibitors in HNSCC.

Main Methods:

  • Immunohistochemistry and western blot to assess RET levels.
  • In vitro and in vivo assays (cell proliferation, migration, invasion, serial transplantation) to evaluate RET's role.
  • Analysis of EGFR phosphorylation and downstream signaling pathways.

Main Results:

  • Elevated RET levels in HNSCC correlate with larger tumor size, advanced stage, and poorer survival.
  • RET knockdown inhibited HNSCC cell proliferation and invasion.
  • RET inhibition reduced EGFR phosphorylation and downstream signaling, increasing sensitivity to erlotinib.

Conclusions:

  • RET signaling plays a significant role in HNSCC progression.
  • Inhibiting RET signaling offers a potential therapeutic strategy to improve erlotinib efficacy in HNSCC.
  • Preclinical data support RET inhibition as a targeted approach for HNSCC treatment.
Keywords:
EGFRHNSCCRETTKI resistance

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