Chapter 2 - Targeting the Hepatocyte Growth Factor Receptor to Overcome Resistance to Targeted Therapies

Abstract

The hepatocyte growth factor (HGF) and its tyrosine kinase receptor cMET (MET proto-oncogene) entered into the spotlight mainly as a bypassing pathway for other targeted therapies (e.g., therapies targeting epidermal growth factor receptor). However, the HGF-cMET signaling axis can be oncogenic by itself. Aberrations in HGF-cMET occur in many cancer types, such as non-small-cell lung cancer, pancreatic cancer, and renal carcinoma. This resulted in the development of several inhibitors targeting this signaling axis. Biomarkers for these targeted therapies include cMET amplification and cMET exon 14 skipping. Activation of cMET by HGF results in the activation of several downstream pathways, among which are the mitogen-activated protein kinase cascade and phosphatidylinositol-3-kinase-Akt signaling. During embryogenesis, they control the development of tubules and are involved in the migration and invasion of several cell types. These functions are mirrored in cancer growth, whereby cMET is a known activator of cell migration and metastasis. Therefore, in this chapter, we start by describing the road to discovery, the functions in development, and explain the HGF-cMET signaling in detail. Next we focus on HGF-cMET in cancer, describing the possible aberrations and providing an overview of inhibitors (under development). Finally, we pay attention to the role of HGF-cMET as a resistance mechanism against other (targeted) therapies.