Abstract
The management of locally advanced head and neck squamous cell carcinoma (HNSCC) with Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), achieves only moderate response rates, and clinical trials that evaluated EGFR-blockade with tyrosine kinase inhibitors (TKI) yielded disappointing results. Inter-tumor heterogeneity may hinder the therapeutic efficiency of anti-EGFR treatments. HNSCC heterogeneity was addressed in several studies, which all converged towards the definition of molecular subgroups. They include the basal subgroup, defined by the deregulated expression of factors involved in the EGFR signaling pathway, including the epiregulin EGFR ligand encoded by the EREG gene. These observations indicate that basal tumors could be more sensitive to anti-EGFR treatments. To test this hypothesis, we performed a screen of a representative collection of basal versus non-basal HNSCC cell lines for their sensitivity to several anti-EGFR drugs (Cetuximab, Afatinib, and Gefitinib), tested as monotherapy or in combination with drugs that target closely-linked pathways [Mitogen-activated protein kinase kinase/extracellular signal–regulated kinases (MEK), mammalian Target of Rapamycine (mTOR) or Human Epidermal growth factor Receptor 2 (HER2)]. Basal-like cell lines were found to be more sensitive to EGFR blockade alone or in combination with treatments that target MEK, mTOR, or HER2. Strikingly, the basal-like status was found to be a better predictor of cell response to EGFR blockade than clinically relevant mutations [e.g., cyclin-dependent kinase Inhibitor 2A (CDKN2A)]. Interestingly, we show that EGFR blockade inhibits EREG expression, and that EREG knock-down decreases basal cell clonogenic survival, suggesting that EREG expression could be a predictive functional marker of sensitivity to EGFR blockade in basal-like HNSCC.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in the world, with over 600,000 cases diagnosed each year [1]
Signaling pathway analysis across the public datasets established that basal tumors display up-regulation of genes involved in the epidermal growth factor receptor (EGFR) signaling pathway (amphiregulin (AREG), EREG), adaptation to hypoxia (Hypoxia Inducible Factor- 1α (HIF1A), Carbonic Anhydrase 9 (CA9)), and differentiation/keratinization of basal epithelial cells (Cadherin 3 (CDH3), Cadherin 13 (CDH13))
We confirmed this hypothesis with a collection of head and neck squamous cell carcinoma (HNSCC) cell lines that resemble basal or non-basal tumors, based on their molecular features reported in several databases (the Genomics of Drug Sensitivity in Cancer (GDSC)
Summary
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in the world, with over 600,000 cases diagnosed each year [1]. They encompass a heterogeneous group of malignancies that arise from the epithelium of the upper aero-digestive tract (oral cavity, pharynx, and larynx). Cetuximab (a monoclonal antibody that targets EGFR (epidermal growth factor receptor)) is the only targeted therapy used for the management of locally advanced HNSCC. More than 10 years after the Food and Drug Administration approval of Cetuximab, alone or in combination with radiotherapy or chemotherapy, HNSCC patient outcome has only been moderately improved [4]
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