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.