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Qureshy et al. J Cancer Metastasis Treat 2020;6:27 I http://dx.doi.org/10.20517/2394-4722.2020.58 Page 11 of 18
[50]
activation and reduced OSM receptor expression . Furthermore, treatment with filgotinib inhibited
resistance to targeted therapy such as MEK, EGFR tyrosine kinase, and ALK inhibitors. In NCI-H889
lung cancer cells, derived from a metastatic site, filgotinib inhibited STAT3 activation [163] . In vivo, filgotinib
treatment reduced metastatic seeding of NCI-H889-derived tumors. In a breast cancer cell line, filgotinib
inhibited STAT3 phosphorylation; in combination with a histone deacetylase inhibitor, there was increased
apoptosis in breast cancer cells as well as tumor growth inhibition in mice harboring breast cancer
tumors [164] .

Lestaurtinib
Lestaurtinib is a multitarget inhibitor that has activity against JAK2, in addition to fms-like tyrosine kinase
tyrosine 3 (FLT3) and tropomyosin related kinase B (TrkB) [165] . Its impact on the JAK/STAT pathway has
been studied clinically in myeloproliferative disorders, but trials in solid tumors such as neuroblastoma
focus on its activity against other targets such as TrkB. One preclinical study showed that lestaurtinib
treatment of anaplastic thyroid cancer cell lines inhibited STAT5 phosphorylation/activation, cell
proliferation, cell survival, and cell migration, in addition to tumor growth in in vivo models [166] .

Peficitinib
Peficitinib is a JAK1/2/3 and TYK2 inhibitor, approved in Japan in 2019 for rheumatoid arthritis after
Phase III clinical trials demonstrated a reduction in symptoms and minimal toxicity compared to placebo
in clinical trials [167,168] . Only one study to date has reported its potential use in solid tumors [169] . In ovarian
cancer stem cells engineered to overexpress OCT4, peficitinib induced apoptosis and inhibited proliferation
in conjunction with JAK1 inhibition.

CONCLUSION
Aberrant JAK/STAT signaling is associated with solid tumor development and progression. However,
unlike hematopoietic malignancies which harbor activating JAK mutations that lead to increased JAK/
STAT signaling, the majority of solid tumors that demonstrate increased JAK/STAT signaling lack
somatic JAK mutations. Studies in preclinical cancer models of solid tumors collectively show that small
molecule JAK inhibitors inhibit activation of STATs, particularly STAT3, in conjunction with inhibition of
proliferation and tumor growth. The majority of JAK inhibitors tested in clinical trials, with the exception
of AZD1480, were found to be safe and well-tolerated. Among these, ruxolitinib is the only inhibitor to date
to demonstrate responses in early stage trials. While Phase II trial results in pancreatic cancer suggested
an association between elevated CRP and response to ruxolitinib plus capecitabine, these findings were
not seen in the Phase III trials [89,90] . In patients with elevated CRP, ruxolitinib combined with capecitabine
[91]
was associated with improved health-related quality of life in breast cancer . Additionally, treatment
[96]
of patients with NSCLC with ruxolitinib plus afatinib resulted in partial responses and stable disease .
However, most trials testing ruxolitinib exhibited disappointing results, and several were terminated early;
this could possibly be explained by JAK inhibition impeding immune cell function, which may counteract
some of the drug’s other anti-cancer effects [170] . It is clear that only a subset of solid tumors is likely to be
sensitive to JAK inhibition. Candidate predictive biomarkers to date include elevated CRP in pancreatic
and breast cancers, PTPRT/D mutations in HNC, and a JAK1 S703I mutation in HCC, and assessments of
biologically plausible biomarkers that predict clinical responses are needed [40,54,55,89,91] . The JAK inhibitors
fedratinib, filgotinib, and peficitinib have been shown to abrogate JAK/STAT signaling and induce anti-
tumor effects in solid tumor cell lines, but, to date, there are no clinical trials investigating these agents
in solid tumors; lestaurtinib has been tested clinically in solid tumors for its activity against other targets
not directly involved in the JAK/STAT pathway. Ruxolitinib, tofacitinib, fedratinib, and peficitinib are
JAK inhibitors already approved for other indications, making them especially attractive options as they
are known to be well-tolerated. Further investigation of JAK inhibitors in clinical trials is warranted to
determine the therapeutic potential in solid tumors.