[Frontiers in Bioscience 18, 520-542, January 1, 2013]

Molecular markers of response and resistance to EGFR inhibitors in head and neck cancers

Carol Box1, Miriam Zimmermann1, Suzanne Eccles1, 2

1Tumour Biology and Metastasis Team, Division of Cancer Therapeutics, McElwain Laboratories, The Institute of Cancer Research, Cotswold Road, Belmont, Sutton, Surrey, SM2 5NG, UK, 2Cancer Research UK Cancer Therapeutics Unit


1. Abstract
2. Introduction
2.1. Characteristics of squamous cell carcinoma of the head and neck (SCCHN)
2.1.1. The SCCHN microenvironment
2.2. Receptor tyrosine kinase (RTK) therapeutic targets in SCCHN
2.2.1. The EGFR family in SCCHN: validation as targets
3. First generation tyrosine kinase inhibitors (TKI) of EGFR
3.1. TKIs as SCCHN therapies
3.1.1. Molecular indicators of response to TKIs
3.2. Resistance to TKIs: markers and mechanisms
3.2.1. EGFR-mediated
3.2.2. Receptor switching
3.2.3. Non-receptor-mediated
3.3. Therapeutic strategies to overcome resistance
4. Next generation inhibitors of ERBB signalling
4.1. EGFR family irreversible TKIs
4.2. Multi-targeted inhibitors
4.3. HSP90 inhibitors
5. Therapeutic antibodies targeting the EGFR
5.1. Cetuximab: an anti-EGFR monoclonal antibody (mAb) approved for therapy in SCCHN
5.2. Additional EGFR therapeutic antibodies and new applications in SCCHN
5.3. Markers of response and resistance to monoclonal antibodies
6. Summary and perspectives
7. Acknowledgements
8. References


Receptor tyrosine kinases (RTK) are key targets for novel cancer therapeutics since they activate multiple oncogenic signalling pathways. Also, they are inherently 'druggable' due to their small ATP-dependent kinase domains (inhibitable by small molecules) and cell surface location which renders them accessible to monoclonal antibody-based therapies. The epidermal growth factor receptor (EGFR) is overexpressed in the majority of SCCHN cases and this review focuses primarily on the progress made in targeting the EGFR for the therapy of SCCHN by both small molecules and antibody-based therapies. We then discuss the overlapping and distinct molecular markers of response, innate or acquired resistance to each modality, and how these may be overcome. We also consider other RTKs overexpressed in this disease that may impact on responses and/or provide additional targets for combination therapy.