Receptor tyrosine kinases: Characterisation, mechanism of action and therapeutic interests for bone cancers

Abstract

Bone cancers are characterised by the development of tumour cells in bone sites, associated with a dysregulation of their environment. In the last two decades, numerous therapeutic strategies have been developed to target the cancer cells or tumour niche. As the crosstalk between these two entities is tightly controlled by the release of polypeptide mediators activating signalling pathways through several receptor tyrosine kinases (RTKs), RTK inhibitors have been designed. These inhibitors have shown exciting clinical impacts, such as imatinib mesylate, which has become a reference treatment for chronic myeloid leukaemia and gastrointestinal tumours. The present review gives an overview of the main molecular and functional characteristics of RTKs, and focuses on the clinical applications that are envisaged and already assessed for the treatment of bone sarcomas and bone metastases.

Keywords: Bone metastasis; Bone sarcoma; Growth factor; Inhibitor; Receptor tyrosine kinase; Therapy.

Fig. 1

General organisation of the molecular domains that make up the RTKs. RTKs are characterised by the dimerisation of two receptor chains with an N-terminal (N) extracellular domain (ECM), and a C-terminal (C) intracellular domain (ICD). The extracellular domain is implicated in the recognition of the dimeric ligands and the formation of the receptor chain dimerisation process. The extracellular domain is associated with ligand recognition and is composed of various domains depending on the RTK class. The transmembrane-domain is composed of an α-helix chain, which contributes to the stabilisation of the dimeric receptor chains. The binding of a dimeric ligand (in red) to the extracellular domains of the receptor chains strengthens the stabilisation of the receptor chains, which are auto-phosphorylated through their tyrosine kinase domains and then transduced in specific downstream signalling pathways.

Fig. 2

Main signalling pathways activated by the ligand-induced RTK auto-phosphorylations. The phosphorylation cascades initiated by the RTK phosphorylations lead to the activation of numerous transcription factors, which consequently control the regulation of many physiological processes.

Fig. 3

The negative feedback loops regulating RTK activation. The window of time required for inducing mRNA and protein synthesis after RTK activation is between 15 and 90 min. These mechanisms are tightly regulated by negative feedback loops. Indeed, the phosphorylation cascade induced by RTK activation leads to the activation of numerous transcription factors and simultaneously their repressors. The translocation of the various transcription factors can also induce the expression of transcriptional repressors or phosphases, which in turn can repress the corresponding transcription factors and/or the upstream kinase activites. +: activation; –: repression.