Abstract
The epidermal growth factor receptor (EGFR) inhibitor cetuximab is the only FDA-approved oncogene-targeting therapy for head and neck squamous cell carcinoma (HNSCC). Despite variable treatment response, no biomarkers exist to stratify patients for cetuximab therapy in HNSCC. Here, we applied unbiased hierarchical clustering to reverse-phase protein array molecular profiles from patient-derived xenograft (PDX) tumors and revealed 2 PDX clusters defined by protein networks associated with EGFR inhibitor resistance. In vivo validation revealed unbiased clustering to classify PDX tumors according to cetuximab response with 88% accuracy. Next, a support vector machine classifier algorithm identified a minimalist biomarker signature consisting of 8 proteins — caveolin-1, Sox-2, AXL, STING, Brd4, claudin-7, connexin-43, and fibronectin — with expression that strongly predicted cetuximab response in PDXs using either protein or mRNA. A combination of caveolin-1 and Sox-2 protein levels was sufficient to maintain high predictive accuracy, which we validated in tumor samples from patients with HNSCC with known clinical response to cetuximab. These results support further investigation into the combined use of caveolin-1 and Sox-2 as predictive biomarkers for cetuximab response in the clinic.
Highlights
The incidence of head and neck squamous cell carcinoma (HNSCC) is increasing, with few FDA-approved targeted therapy options
We identified an 8-gene signature able to predict cetuximab response using either protein or mRNA measurements, which we validated on an independent HNSCC patient-derived xenograft (PDX) cohort [9]
An unsupervised hierarchical clustering approach was used to group the PDXs based on their protein expression signatures (Figure 1A, Supplemental Figure 1A, and Supplemental Table 3), which yielded 2 distinct PDX clusters defined by 2 biomarker clusters (Figure 1B; Supplemental Figure 1, B and C; and Supplemental Table 3)
Summary
The incidence of head and neck squamous cell carcinoma (HNSCC) is increasing, with few FDA-approved targeted therapy options. A monoclonal antibody directed against the epidermal growth factor receptor (EGFR), was approved by the FDA in 2006 as the first molecular targeted agent for HNSCC. It performed favorably in a series of clinical trials, leading to approval in combination with radiation as firstline therapy for locoregionally advanced HNSCC, in conjunction with platinum-based therapy and fluorouracil for recurrent or metastatic disease, or as a single agent in recurrent or metastatic disease refractory to platinum-based therapy [1,2,3]. Characterizing the molecular tumor profiles that correlate with cetuximab response in PDX models of HNSCC may enable the identification of biomarkers for treatment stratification
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