AXL regulates cetuximab resistance in HNSCC and NSCLC


Cetuximab, the EGFR antibody, has been a useful treatment for numerous cancers, however, the drug resistance is a common clinnical problem. Previous studies showed AXL, a receptor involved in anti-EGFR tyrosine kinase inhibitors (TKI) resistance, was highly expressed in head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC) models, which have cetuximab resistance (CtxR). Brand et al. demonstrated that AXL-EGFR signaling positive feedback loop is one of the mechanism of developing cetuximab resistance. The article was published in Cancer Research.


In  CtxR  cells, AXL overexpression enhances cell proliferation, EGFR activation and MAPK signaling. On the other hand, EGFR directly mediated the transcription of AXL via MAPK signaling and the transcription factor c-Jun. Therefore, EGFR and AXL form a positive feedback loop in CtxR  cells. Cells gain cetuximab resistance due to the increase of AXL activity, either by AXL overexpression or EGFR ligands stimulation in cetuximab-sensitive cells or xenografted tumors, even those from patient with HCSCCs. These results suggest that AXL promotes cetuximab resistance, and may act as a therapeutic target for treatment of cetuximab-resistance cancers.


Cancer Res. 2014 Sep 15;74(18):5152-64.