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Caveolin-1 and Sox-2 are predictive biomarkers of cetuximab response in head and neck cancer
Mehdi Bouhaddou, … , Nevan J. Krogan, Jennifer R. Grandis
Mehdi Bouhaddou, … , Nevan J. Krogan, Jennifer R. Grandis
Published September 21, 2021
Citation Information: JCI Insight. 2021;6(20):e151982. https://doi.org/10.1172/jci.insight.151982.
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Research Article Therapeutics

Caveolin-1 and Sox-2 are predictive biomarkers of cetuximab response in head and neck cancer

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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.

Authors

Mehdi Bouhaddou, Rex H. Lee, Hua Li, Neil E. Bhola, Rachel A. O’Keefe, Mohammad Naser, Tian Ran Zhu, Kelechi Nwachuku, Umamaheswar Duvvuri, Adam B. Olshen, Ritu Roy, Aaron Hechmer, Jennifer Bolen, Stephen B. Keysar, Antonio Jimeno, Gordon B. Mills, Scott Vandenberg, Danielle L. Swaney, Daniel E. Johnson, Nevan J. Krogan, Jennifer R. Grandis

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Figure 1

Hierarchical clustering of protein markers reveals 2 HNSCC PDX subtypes.

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Hierarchical clustering of protein markers reveals 2 HNSCC PDX subtypes....
(A) Schematic of PDX derivation, reverse-phase protein array (RPPA), and clustering analysis. Primary patient HNSCC tumors were excised and implanted into NOD/SCID γ mice. Lysates of the xenografted cells were molecularly profiled using RPPA for 247 proteins and then analyzed via an unsupervised hierarchical clustering analysis. (B) Unbiased hierarchical clustering yields 2 PDX clusters (rows) defined by differential expression of candidate biomarker groups 1 and 2 (columns). Primary site, sex, HPV status, American Joint Committee on Cancer (AJCC) tumor stage, and age of patients in years are indicated (right). Signal is defined as the median-centered chemiluminescent signal from the RPPA assay.

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