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Page 2 of 18 Qureshy et al. J Cancer Metastasis Treat 2020;6:27 I http://dx.doi.org/10.20517/2394-4722.2020.58

INTRODUCTION
The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is
[1,2]
implicated in the development and progression of many cancers . Hyperactivation of STAT transcription
factors, has been reported in both hematologic malignancies and solid tumors, including cancers of the
breast, lung, liver, head and neck, and stomach, among others [3-8] . For many of these cancers, increased
activation of the JAK/STAT signaling pathway is associated with a worse prognosis, including increased
recurrence and reduced overall survival [1,9,10] . Given the strong association between JAK/STAT hyperactivity
and the development and prognosis of multiple cancers, STATs and their upstream activators, JAKs, are
being extensively explored as targets for cancer therapy [1,11-13] .

Certain hematologic malignancies such as myeloproliferative neoplasms are associated with specific
[14]
JAK mutations that serve as predictive biomarkers for JAK-targeted therapy . The majority of cases of
polycythemia vera, essential thrombocytopenia, and myelofibrosis are characterized by an activating valine
[15]
to phenylalanine mutation in JAK2 (JAK2 V617F) that drives the development of these neoplasms .
Clinical trials studying the impact of ruxolitinib, a selective JAK1/2 inhibitor, on polycythemia vera
and myelofibrosis demonstrated significant improvement in patient outcomes, leading to Food and
Drug Administration (FDA) approval and widespread use of this agent for these diseases [16-22] . However,
mutations in the JAK/STAT pathway are rare in solid tumors, and the role of JAK and/or STAT inhibitors
for the treatment of solid tumors is incompletely understood. In this review, we describe the rationale for
targeting the JAK/STAT pathway in solid tumors and summarize preclinical studies and clinical trials to
date that evaluate the impact of agents targeting this pathway.

JAK/STAT SIGNALING
Ligands, particularly cytokines and growth factors, provide the initial stimulus for activating the JAK/
[23]
STAT pathway . Cytokines bind to their corresponding transmembrane receptor subunits, resulting in
[24]
multimerization with other subunits and close physical interactions of receptor-associated JAKs . The
[25]
JAK family of tyrosine kinases consists of JAK1, JAK2, JAK3, and TYK2 . Once the receptor-associated
JAKs are placed in close proximity, they become activated via trans-phosphorylation . Activated JAKs
[24]
phosphorylate tyrosine residues on the cytoplasmic region of the cytokine receptor to provide docking
sites for the Src Homology 2 (SH2) domain of STAT proteins. The binding of a member of the STAT
family of proteins (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6) to the phosphorylated
receptor intracellular domain results in JAK-mediated tyrosine phosphorylation and activation of the
[26]
STAT protein [Figure 1] . In the case of receptors with intrinsic tyrosine kinase activity (e.g., epidermal
growth factor receptor, EGFR), ligand binding results in receptor autophosphorylation of tyrosine residues
which serve as the docking sites for STATs, and the bound STATs are directly phosphorylated/activated by
the receptor tyrosine kinase. Activated STATs dimerize and translocate into the nucleus where they serve
as transcription factors, inducing the expression of genes that regulate cellular proliferation, survival, and
invasion, as well as the host immune response [14,24,27,28] .

The JAK/STAT signaling pathway is modulated by several negative regulators . Members of the
[29]
suppressors of cytokine signaling (SOCS) family of proteins, such as SOCS1 and SOCS3, are inhibitory
against JAKs, while cytokine-inducible SH2-containing protein (CIS) blocks STAT binding sites
on receptor proteins [29,30] . Another family of inhibitory molecules, the protein inhibitor of activated
STAT (PIAS) proteins, inhibit the binding of STATs to response elements in target genes [29,31] . Protein
tyrosine phosphatase receptors (PTPRs), specifically PTPRT, PTPRD, and PTPRK, have been shown to
dephosphorylate STAT3, resulting in STAT3 inactivation; a handful of non-receptor PTPs harbor a similar
function [32-37] . Increased activity of JAKs and STATs coupled with decreased activity of negative regulators
can lead to an upregulation of pro-proliferative, anti-apoptotic, and immunosuppressive proteins,
potentially driving oncogenesis.