Receptor Tyrosine Kinase (RTK) Inhibitors in Head and Neck Cancer

Tumour Biology and Metastasis Team

Section: Cancer Research UK Cancer Therapeutics Unit

(In collaboration with the Head and Neck Unit, Royal Marsden Hospital)

Epidermal growth factor receptor (EGFR) is overexpressed in 80–100% of squamous cell carcinomas of the head and neck (SCCHN) and is an adverse, independent predictor for survival in this disease. We have optimised assays of key downstream molecular mediators of cell proliferation, apoptosis, invasion and angiogenesis suitable for use with surrogate tissues (serum/skin) and tumour samples. We have characterised an extensive panel of SCCHN cell lines including those recently derived from patients for RTK status and response to inhibitors.

In addition we have generated a cell line with acquired resistance to gefitinib (Iressa®), a small molecule EGFR tyrosine kinase inhibitor. Using these cell lines, we are currently investigating biomarkers which may determine intrinsic or acquired resistance to gefitinib. We have found that factors such as EGFR gene mutation (reported to determine sensitivity in non-small cell lung cancer) are not determinants of sensitivity in SCCHN. We are now comparing the molecular profiles of cell lines which are particularly sensitive to gefitinib with those displaying intrinsic or acquired resistance to seek novel indicators of response.

The 'INHANCE' Phase II clinical trial aims to determine the efficacy of gefitinib in combination with neoadjuvant chemotherapy in patients with locally advanced SCCHN. This trial has exceeded 50% accrual and pre- and post-treatment clinical samples will be analysed with the aim of identifying changes in key biomarkers prioritised from preclinical studies.