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

Aberrant EGFR signaling drives non-small cell lung cancer (NSCLC) development, and despite the success of tyrosine kinase inhibitor (TKI) therapies in treating NSCLC, TKI resistance remains a major obstacle. Here, we report that the chemokine-like transmembrane protein CMTM6 is physically associated with EGFR. CMTM6 is shown to be co-localized with EGFR in recycling endosomes that are marked by RAB11, thereby preventing EGFR from lysosome-mediated degradation in NSCLC cells. The level of CMTM6 is elevated in NSCLC, and high expression of CMTM6 is associated with enhanced colocalization of CMTM6 with EGFR and RAB11 in NSCLC tumors and correlated with a poor prognosis in NSCLC patients. A CMTM6-targeting nanobody is developed and administration of this agent leads to blocking of the CMTM6-EGFR interaction, reduction of the EGFR protein level, and inhibition of the proliferation of TKI-resistant NSCLC cells in vitro and suppression of the growth of EGFR-TKI-resistant NSCLC in both cell line-derived xenografts and patient-derived xenograft models. The study indicates that CMTM6 is a stabilizer of EGFR in endocytic trafficking and provides evidence to support targeting CMTM6 as a potential therapeutic strategy to overcome TKI resistance in NSCLC treatment.

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Publication Details

Journal
Advanced Science
Published
2025-06-16
DOI
https://doi.org/10.1002/advs.202410945
Citations
3
Primary Topic
Peptidase Inhibition and Analysis
Type
article
Field-Weighted Citation Impact
3.14

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article

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

Sen Qin, Sudun Guan, Yong Geng, Qinghua Li et al.
3 citations
Advanced Science
Peptidase Inhibition and Analysis
3.14
article

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

Sen Qin, Sudun Guan, Yong Geng, Qinghua Li, Hui Xue, Feiya Suo, Jichuan Wang, Enrun Zheng, Yongfeng Shang, Luyang Sun, Yu Gao, Yanhua Liu, Yongsheng Wang, Lin He, Lingyun Li, Wenling Han, Xia Lu, Chunyu Yu, Haimeng Li
article en
3 citations

Abstract

Aberrant EGFR signaling drives non-small cell lung cancer (NSCLC) development, and despite the success of tyrosine kinase inhibitor (TKI) therapies in treating NSCLC, TKI resistance remains a major obstacle. Here, we report that the chemokine-like transmembrane protein CMTM6 is physically associated with EGFR. CMTM6 is shown to be co-localized with EGFR in recycling endosomes that are marked by RAB11, thereby preventing EGFR from lysosome-mediated degradation in NSCLC cells. The level of CMTM6 is elevated in NSCLC, and high expression of CMTM6 is associated with enhanced colocalization of CMTM6 with EGFR and RAB11 in NSCLC tumors and correlated with a poor prognosis in NSCLC patients. A CMTM6-targeting nanobody is developed and administration of this agent leads to blocking of the CMTM6-EGFR interaction, reduction of the EGFR protein level, and inhibition of the proliferation of TKI-resistant NSCLC cells in vitro and suppression of the growth of EGFR-TKI-resistant NSCLC in both cell line-derived xenografts and patient-derived xenograft models. The study indicates that CMTM6 is a stabilizer of EGFR in endocytic trafficking and provides evidence to support targeting CMTM6 as a potential therapeutic strategy to overcome TKI resistance in NSCLC treatment.

Advanced ScienceVol. 12(27)
Hangzhou Normal University (CN), Chinese Academy of Sciences (CN), Peking University (CN), Sichuan University (CN), Shanghai Institute of Materia Medica (CN), Peking University People's Hospital (CN), State Key Laboratory of Natural and Biomimetic Drugs (CN)
National Natural Science Foundation of China, Ministry of Science and Technology of the People's Republic of China, Science and Technology Commission of Shanghai Municipality, Natural Science Foundation of Beijing Municipality, Peking University, National Key Research and Development Program of China
Good health and well-being
Openalex Percentile: Top 8%
Peptidase Inhibition and Analysis
3.14
DOIOpen Access PDFOpenAlex
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