-Amplified and -A159V Hotspot-Mutated Head and Neck Cancer Sensitive to the Rac Inhibitor EHop-016 In Vivo: A Proof-of-Concept Study.

aberrations in head and neck squamous cell carcinoma (HNSCC) remain clinically inactionable today. Here, we investigated the clinical significance and potential druggability of genomic aberrations in HNSCC. Notably, HPV(-)HNSCC patients bearing the unique HNSCC-prevalent -A159V hotspot mutation, P29S hotspot and G-box domain mutations, and copy number increases all displayed dismal overall survival (TCGA-HNSCC). Here, we demonstrated that all five HNSCC patient-relevant aberrations tested (A159V and P29S hotspot mutations, K116N, G15S, and N39S) could significantly drive HNSCC tumoroid growth and/invasion, with A159V, P29S, and K116N mutants being the most potent drivers. Interestingly, transcriptomics analyses revealed that mutations and copy increase could both drive PI3K pathway activation, with the A159V mutant associated with the prominent intra-tumoral upregulation of phospho-RPS6(Ser235/236) in patient tumors. Importantly, proof-of-principle Rac targeting with EHop-016 resulted in remarkable antitumor activity in vivo against -A159V-mutated and -amplified HNSCC patient-derived xenografts (PDXs) and/engineered models. Lastly, melanoma and endometrial xenograft models bearing endogenous -amplification and -A159V mutation were also sensitive to EHop-016 targeting. In principle, genomic aberrations in HNSCC can be potentially harnessed for precision drugging.