Epidermal growth factor receptor (EGFR) inhibitors are approved by the Food and Drug Administration (FDA) but remain under active clinical investigation for the treatment of both newly diagnosed and recurrent/metastatic
head and neck squamous cell carcinoma (
HNSCC). Despite EGFR expression in the majority of
HNSCC tumors, the levels of total or phosphorylated EGFR have not consistently been correlated with a response to EGFR targeting agents. The lack of predictive
biomarkers represents a major obstacle to successful use of these drugs. Activation of
phosphatidylinositol 3-kinase (PI3K) signaling by mutation of the PIK3CA oncogene represents a plausible mechanism for EGFR inhibitor drug resistance. We compared the impact of EGFR inhibitors, alone or in combination with non-steroidal anti-inflammatory drugs (
NSAIDs), in preclinical
HNSCC models harboring mutant versus wild-type PIK3CA. Our results demonstrate additive or synergistic effects of
NSAIDs and EGFR inhibitors in vitro and in vivo in PIK3CA-mutated
HNSCC models. These findings suggest that the addition of
NSAIDs to EGFR inhibitors for the treatment of
HNSCC may represent a promising therapeutic strategy in PIK3CA-mutated
cancers.