Biomarkers for an effective and cost-effective use of anti-EGFR biotherapeutics for the treatment of head and neck cancers

Datum: 17 juni 2014

Locatie: University of Antwerp - Campus Drie Eiken - Building Q - Promotiezaal - Universiteitsplein 1 - 2610 Wilrijk

Tijdstip: 17 uur

Organisatie / co-organisatie: Faculty of Medicine and Health Sciences

Promovendus: Carolien Boeckx

Promotor: Prof F. Lardond and Dr M. Baay

Korte beschrijving: PhD defense Carolien Boeckx - Faculty of Medicine and Health Sciences

Abstract: Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cause of cancer death worldwide. In only 50% of the patients the current conventional treatment strategies are effective, underscoring the need for new approaches to treat this malignancy. Therefore, personalized medicine using targeted therapies will hopefully achieve the much-needed progress in HNSCC.

Increased expression of the epidermal growth factor receptor (EGFR) is frequently observed in HNSCC and initiates important cellular processes. Consequently, EGFR targeting therapy is one of the most promising molecular therapeutics. However, drug resistance limits the clinical efficacy of the anti-EGFR monoclonal antibody cetuximab and no predictive biomarker has entered the clinic yet. Unraveling the underlying mechanisms of cetuximab resistance is of major importance.

In this dissertation, mechanisms of drug resistance were examined from different point of views.

First, Caucasian HNSCC patients were screened for mutations in genes involved in the EGFR pathways. In our population, no EGFRvIII and only two silent EGFR tyrosine kinase mutations were detected. Due to the discrepancy between high resolution melting analysis and sequencing results, KRAS mutations frequency varied from 0.0% to 7.0%.

Second, the effect of the hypoxic tumor microenvironment on anti-EGFR therapy in three cetuximab-sensitive cell lines was investigated. Our results suggest that hypoxia probably does not contribute to anti-EGFR drug resistance as both anti-EGFR therapeutics cetuximab and erlotinib maintained their efficacy after exposure to both 24 and 72 hours of reduced oxygen tension in the HNSCC cell lines.

Finally, gene expression profiles of HNSCC cell lines with different response towards cetuximab revealed that resistant cells were characterized by loss of epithelial keratins and claudins and an increased expression of mesenchymal markers. However, more attention was paid to the divergent expression of the MAPK pathway, especially downregulation of DUSP5, DUSP6 and upregulation of AURKB, HB-EGF and IL8. Furthermore, combination therapy in vitro was able to overcome this resistance.

In general, the novel findings presented in this dissertation provide new insights in the underlying mechanisms of anti-EGFR therapeutic resistance in HNSCC. These observations can form a solid basis for further in vivo and clinical studies on this topic, in order to make progress in the treatment of HNSCC.