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A CMTM6 Nanobody Overcomes EGFR-TKI Resistance in Non-Small Cell Lung Cancer

Lu Xia1, Jichuan Wang2, Hui Xue3

  • 1Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University International Cancer Institute, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing, 100191, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|June 16, 2025
PubMed

Insights

Chemokine-like transmembrane protein 6 (CMTM6) stabilizes epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC). Targeting CMTM6 may overcome resistance to tyrosine kinase inhibitor (TKI) therapies in NSCLC patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Aberrant epidermal growth factor receptor (EGFR) signaling drives non-small cell lung cancer (NSCLC) development.
  • Tyrosine kinase inhibitor (TKI) therapies are effective against NSCLC, but resistance remains a significant clinical challenge.

Purpose of the Study:

  • To investigate the role of chemokine-like transmembrane protein 6 (CMTM6) in EGFR regulation and its potential as a therapeutic target in NSCLC.
  • To determine if targeting the CMTM6-EGFR interaction can overcome TKI resistance in NSCLC.

Main Methods:

  • Co-immunoprecipitation to assess CMTM6-EGFR interaction.
  • Immunofluorescence microscopy to analyze co-localization of CMTM6, EGFR, and RAB11 in NSCLC cells and tumors.
  • Development and testing of a CMTM6-targeting nanobody in vitro and in vivo xenograft models.

Main Results:

  • CMTM6 physically associates with and co-localizes with EGFR in RAB11-positive recycling endosomes, preventing EGFR lysosomal degradation.
  • Elevated CMTM6 expression in NSCLC correlates with poor prognosis and enhanced CMTM6-EGFR-RAB11 co-localization.
  • A CMTM6-targeting nanobody blocked CMTM6-EGFR interaction, reduced EGFR levels, and inhibited proliferation of TKI-resistant NSCLC cells and tumor growth in vivo.

Conclusions:

  • CMTM6 acts as an EGFR stabilizer by modulating its endocytic trafficking.
  • Targeting CMTM6 represents a promising therapeutic strategy to overcome EGFR-TKI resistance in NSCLC.
Keywords:
CMTM6EGFREGFR‐TKIs resistanceNSCLCnanobody

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