NSAIDs Overcome PIK3CA Mutation-Mediated Resistance to EGFR Inhibition in Head and Neck Cancer Preclinical Models

SIMPLE SUMMARY: Epidermal growth factor receptor (EGFR) inhibitors are approved by the Food and Drug Administration (FDA) for the treatment of several cancers including head and neck squamous cell carcinoma (HNSCC). It has been reported that activating mutations in PIK3CA, which are relatively common, may contribute to EGFR inhibitor resistance while conferring sensitivity to treatment with non-steroidal anti-inflammatory drugs (NSAIDs). We hypothesized that disruption of PI3K/COX/EGFR crosstalk via COX inhibition would overcome resistance to EGFR inhibition in HNSCC models, particularly in the context of PIK3CA mutation. We found that the combination of NSAIDs and EGFR inhibitors showed additive or synergistic effects in preclinical HNSCC models harboring mutant PIK3CA. Our results suggest that PIK3CA mutation in HNSCC might represent a predictive biomarker for EGFR inhibitors in combination with NSAIDs. ABSTRACT: 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.