Page 299 - Read Online

Page 4 of 18 Qureshy et al. J Cancer Metastasis Treat 2020;6:27 I http://dx.doi.org/10.20517/2394-4722.2020.58

secretion of oncostatin-M (OSM), a member of the IL-6 cytokine family, by cancer-associated fibroblasts
increases STAT3 activity through activation of JAK1 and is a possible mechanism of resistance to targeted
[50]
therapy such as EGFR and MEK inhibitors . STAT3 hyperactivity seen in pancreatic cancers has been
associated with increased IL-22-induced STAT3 signaling and SOCS3 suppression, leading to increased
invasion, migration, and angiogenesis [51-53] . PTPRT, another negative regulator of the JAK/STAT pathway, is
silenced via promoter hypermethylation in many cases of HNC and provides a likely mechanism for STAT3
[54]
[55]
hyperactivation in this cancer . Loss-of-function mutations in PTPRD have also been implicated .
Hyperactivation of STAT3 has been reported in many other solid tumor malignancies, including breast
cancer, HCC, and ovarian cancer, among others [56-58] .

Hyperactivation of other STATs
While less common, hyperactivation of other members of the STAT protein family has been shown in
some solid tumors. STAT1 drives aromatase inhibitor resistance in breast cancer, and is highly expressed
in estrogen receptor-positive, tamoxifen-resistant breast cancer cell lines, indicating it may be a promising
[59]
target in this malignancy . STAT2 is not only highly expressed in ovarian cancer compared to normal
ovarian tissue, but is also associated with metastasis and poor overall survival . STAT2 is also associated
[60]
[61]
with poor overall survival in NSCLC . Hyperactivity of STAT5 is associated with enhanced cell viability,
tumor growth, and recurrence in prostate cancers [62,63] . In colorectal cancer cell lines, elevated levels of
[64]
activated STAT6 are correlated with metastasis and decreased apoptosis .
Collectively, there is ample evidence showing that increased JAK/STAT signaling is associated with
increased cell proliferation, cell survival, immune evasion, recurrence, and drug resistance in solid tumors;
this pathway therefore represents a promising target for therapeutic intervention.

JAK INHIBITORS
While hyperactivation of STATs, primarily STAT3, has been linked to the development and progression
of solid tumors, STATs, similar to other transcription factors, have proven difficult to target directly.
Therefore, upstream activators of STATs, such as JAKs, have been studied in preclinical and clinical settings
as potential therapeutic targets. Several JAK inhibitors have been studied in solid tumors. Figure 2 depicts
JAK inhibitors that are: (1) FDA approved and have been tested clinically in solid tumors [Figure 2A];
(2) not FDA approved, but have been tested clinically in solid tumors [Figure 2B]; and (3) have only been
tested in solid tumor preclinical models. One multitarget agent (lestaurtinib) has been tested clinically for
its activity against other targets [Figure 2C]. To date, there are 10 JAK inhibitors (two of which are FDA
approved for other indications) that have been or are currently being investigated across 45 clinical trials
in patients with solid tumors (excluding trials that have been withdrawn or in which JAK inhibitor was
standard of care in studies investigating other agents) [Table 1]. Some compounds, a few of which are also
FDA approved for other indications, have to date only been studied in solid tumor preclinical models.

JAK inhibitors investigated in clinical trials
Ruxolitinib
The JAK1/2-selective inhibitor ruxolitinib is FDA approved for the treatment of polycythemia vera,
myelofibrosis, and graft versus host disease, and it has been shown to decrease STAT3 activation in
preclinical models of several solid tumors [18,22,65] . Ruxolitinib inhibited STAT3 activation and decreased
[69]
[72]
[71]
[70]
cell growth in breast cancer [66,67] , NSCLC , HNC , esophageal cancer , bladder cancer , HCC ,
[68]
[73]
cervical cancer , and colorectal cancer [74,75] cell lines. In pancreatic cancer cells, ruxolitinib treatment
was also shown to decrease expression of pro-angiogenic genes and impede epithelial-to-mesenchymal
transition [76,77] . In in vivo xenograft models of neuroblastoma [78,79] , HCC (in which there was a JAK1
[40]
[80]
S703I mutation) , and KRAS-mutated lung adenocarcinoma , among others, ruxolitinib treatment