Remarkably, the 8-biomarker signature we present here demonstrates high accuracy for in vivo cetuximab response prediction using PDX samples, and a 2-protein signature consisting of caveolin-1 and Sox-2 retains high accuracy for predicting cetuximab response, both in PDXs and directly in samples from patients with HNSCC. Here, CAV1 is linked to head and neck squamous cell carcinoma.