Mechanisms of receptor tyrosine kinase activation in cancer

Abstract

Receptor tyrosine kinases (RTKs) play an important role in a variety of cellular processes including growth, motility, differentiation, and metabolism. As such, dysregulation of RTK signaling leads to an assortment of human diseases, most notably, cancers. Recent large-scale genomic studies have revealed the presence of various alterations in the genes encoding RTKs such as EGFR, HER2/ErbB2, and MET, amongst many others. Abnormal RTK activation in human cancers is mediated by four principal mechanisms: gain-of-function mutations, genomic amplification, chromosomal rearrangements, and / or autocrine activation. In this manuscript, we review the processes whereby RTKs are activated under normal physiological conditions and discuss several mechanisms whereby RTKs can be aberrantly activated in human cancers. Understanding of these mechanisms has important implications for selection of anti-cancer therapies.

Keywords: Cancer; Chromosomal rearrangement; Mutation; Oncogene; Receptor; Targeted therapy; Tyrosine kinase; Tyrosine kinase inhibitor (TKI).

Fig. 1

Mechanisms of physiological and oncogenic RTK activation. a Schematic representation of RTK activation in normal physiology. RTKs are activated through formation of inter-molecular dimerization in the presence of ligands, resulting in kinase activation and phosphorylation of the receptor C-terminal tail. b Schematic representation of potential gain-of-function mutations in the various subdomains of an RTK. The mutations lead to constitutive activation of the RTK, typically in the absence of ligand. c Overexpression of RTKs – often as a result of genomic amplification of the RTK gene - leads to increased local concentration of receptors

Fig. 2

Mechanisms of oncogenic RTK activation. a Chromosomal rearrangements result in the formation of a hybrid fusion oncoprotein consisting partly of the RTK and partly of the fusion partner, a distinct protein (shown in the figure by the yellow oval). These RTK fusion proteins can be membrane bound (left side of the figure) or cytoplasmic (right side of the figure) depending on the location of the genomic breakpoint. In either case, the result is an activated kinase domain. b Duplication of the tyrosine kinase domain could possibly form an intra-molecular dimer in the absence of ligands, resulting in RTK activation. c Schematic representation of autocrine activation of RTK signaling. Increased local concentration of ligand activated the RTK, resulting in RTK dimerization, increased kinase activity, and phosphorylation of the receptor C-terminal tail