HOXB8 mediates resistance to cetuximab in colorectal cancer cells through activation of the STAT3 pathway

Homeobox B8 (HOXB8) is a member of the HOX family and plays an important role in colorectal cancer development. Cetuximab is one of the most widely used monoclonal antibodies for the treatment of patients with RAS/BRAF wild-type metastatic colorectal cancer (mCRC), but cetuximab resistance frequently occurs during targeted therapy. Currently, the role of HOXB8 in cetuximab-resistant mCRC remains unclear. By comparing cetuximab-sensitive cell lines (SW48) with drug-resistant cell lines (HCT116, CACO2), we found that HOXB8 was highly expressed in cetuximab-resistant cell lines, and furthermore, HOXB8 knockdown enhanced the cytotoxicity of cetuximab in drug-resistant cell lines (HCT116, CACO2) by inhibiting signal transducer and activatorof transcription 3 (STAT3) pathway. Conversely, HOXB8 overexpression attenuated cetuximab-induced growth inhibition in SW48 cells through activation of STAT3 signaling. In conclusion, our findings reveal an important role for HOXB8 in cetuximab-resistant mCRC and suggest that targeting HOXB8 may be an effective therapeutic strategy for certain cetuximab-resistant mCRC patients.