Neddylation as a target in PIK3CA-mutated head and neck cancer.

PIK3CA encodes the catalytic subunit of phosphoinositide 3-kinase (PI3K) enzyme and is the most commonly mutated oncogene in head and neck squamous cell carcinoma (HNSCC). This study aimed to identify potential therapeutic targets in HNSCC harboring mutant PIK3CA. We used CRISPR interference (CRISPRi)-based genome-wide screening methodology to reveal targetable genetic dependencies in PIK3CA-mutated HNSCC. Screening was conducted in an HPV-positive HNSCC cell line, UM-SCC-47, engineered to express the canonical E545K PIK3CA mutant. We identified 34 genes co-dependent on PIK3CA E545K mutation, including 5 genes in the neddylation pathway (NEDD8, NEDD8-MDP-1 and NAE1, USP8, UBA3). Validation experiments confirmed the essential role of NEDD8, NEDD8-MDP-1, and NAE1, indicating a novel regulatory mechanism in PIK3CA E545K-mutated HNSCC. Our findings suggest that PIK3CA mutation may serve as a predictive biomarker for neddylation inhibitor therapy in a subpopulation of HNSCC.