The role of JAK/STAT signalling in the pathogenesis, prognosis and treatment of solid tumours

Abstract

Aberrant activation of intracellular signalling pathways confers malignant properties on cancer cells. Targeting intracellular signalling pathways has been a productive strategy for drug development, with several drugs acting on signalling pathways already in use and more continually being developed. The JAK/STAT signalling pathway provides an example of this paradigm in haematological malignancies, with the identification of JAK2 mutations in myeloproliferative neoplasms leading to the development of specific clinically effective JAK2 inhibitors, such as ruxolitinib. It is now clear that many solid tumours also show activation of JAK/STAT signalling. In this review, we focus on the role of JAK/STAT signalling in solid tumours, examining the molecular mechanisms that cause inappropriate pathway activation and their cellular consequences. We also discuss the degree to which activated JAK/STAT signalling contributes to oncogenesis. Studies showing the effect of activation of JAK/STAT signalling upon prognosis in several tumour types are summarised. Finally, we discuss the prospects for treating solid tumours using strategies targeting JAK/STAT signalling, including what can be learned from haematological malignancies and the extent to which results in solid tumours might be expected to differ.

Figure 1

(A) An overview of the JAK/STAT signalling pathway. (1) Receptor complexes at the cell surface are associated with inactive JAK dimers, which bind close to the transmembrane region of the receptors. (2) Binding of ligand produces a conformational change in the receptor complex that changes the relative position of the JAKs, leading to phosphorylation and activation of their tyrosine kinase activity. The activated JAKs phosphorylate tyrosine residues in the cytoplasmic tails of receptors. (3) Cytoplasmic STATs bind to the phosphorylated receptors, becoming substrates for JAKs. (4) Phosphorylated STATs form dimers and accumulate in the nucleus, where they activate transcription of specific genes. (B) Schematic structure of JAK proteins. The FERM domain (4.1 protein, ezrin, radixin and moesin) mediates the interaction with receptor complexes. The SH2 domain is a protein domain that binds to phosphorylated tyrosine residues. The JH2 pseudokinase domain regulates kinase activity of the JH1 kinase domain. P marks conserved tyrosine residues in JH1 whose phosphorylation is essential for JAK activation. N and C indicate the amino terminus and carboxy terminus. (C) Schematic structure of STAT proteins. The SH2 domain binds phosphorylated tyrosines. The carboxy terminus transactivation domain is required for full transcriptional activation. P marks the conserved tyrosine residue whose phosphorylation is essential for STAT activation.