Overcoming cetuximab resistance in HNSCC: The role of AURKB and DUSP proteins

•Gene expression profiles of cetuximab sensitive and resistant cells were compared.•Cetuximab resistant cells still exhibit RAS–MAPK signaling despite EGFR inhibition.•Resistant cells show up/downregulation of AURKB and DUSP, respectively, as well as features of EMT.•Concomitant ERK and EGFR inhibition can overcome cetuximab resistance.•Strong nuclear AURKB expression by IHC was observed in > 50% of HNSCC patients.

Unraveling the underlying mechanisms of cetuximab resistance in head and neck squamous cell carcinoma (HNSCC) is of major importance as many tumors remain non-responsive or become resistant. Our microarray results suggest that “resistant” cells still exhibit RAS–MAPK pathway signaling contributing to drug resistance, as witnessed by low expression of DUSP5 and DUSP6, negative regulators of ERK1/2, and increased expression of AURKB, a key regulator of mitosis. Therefore, interrupting the RAS–MAPK pathway by an ERK1/2 inhibitor (apigenin) or an AURKB inhibitor (barasertib) might be a new strategy for overcoming cetuximab resistance in HNSCC.