MET and RON Receptor Tyrosine Kinases: Novel Therapeutic Targets in Squamous Cell Carcinoma of the Head and Neck

Susanne   J.   Rogers; Carol      Box; Christopher   M.   Nutting; Peter      Rhys Evans; Kevin   J.   Harrington; Suzanne   A.   Eccles

Abstract

MET (hepatocyte growth factor receptor) and RON (recepteur dorigine Nantaise) are members of the MET proto-oncogene family of receptor tyrosine kinases (RTKs). Signalling from MET or RON activates multiple signalling pathways and ultimately promotes tumorigenesis and the formation of metastases. Mutations in MET have been detected in abundance in squamous cell carcinoma of the head and neck (SCCHN) metastases relative to the primary tumour, suggesting that this is a critical oncogene regulating dissemination. The biological significance of RON in SCCHN is still relatively unexplored. As survival has plateaued for patients with SCCHN, novel therapies with effects on the primary tumour and metastatic disease are urgently required. Small molecule inhibition of MET has been achieved in the pre-clinical setting and future clinical development is an exciting prospect. In this review, we summarise the biology of MET and RON RTKs and their contribution to an invasive tumour phenotype. We highlight their potential as therapeutic targets and address putative roles for MET and RON in resistance to conventional therapy, with particular reference to SCCHN.

Keywords: MET, RON, tyrosine kinase, squamous cell carcinoma of the head and neck, hepatocyte growth factor, macrophage stimulating protein, metastasis, small molecule tyrosine kinase inhibitors