Aberrant activation of signal transducer and activator of transcription (STAT) proteins is associated with the development and progression of solid tumors. However, as transcription factors, these proteins are difficult to target directly. In this review, we summarize the role of targeting Janus kinases (JAKs), upstream activators of STATs, as a strategy for decreasing STAT activation in solid tumors. Preclinical studies in solid tumor cell line models show that JAK inhibitors decrease STAT activation, cell proliferation, and cell survival; in
The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is implicated in the development and progression of many cancers[
Certain hematologic malignancies such as myeloproliferative neoplasms are associated with specific JAK mutations that serve as predictive biomarkers for JAK-targeted therapy[
Ligands, particularly cytokines and growth factors, provide the initial stimulus for activating the JAK/STAT pathway[
JAK/STAT pathway involving receptors lacking intrinsic tyrosine kinase activity: Upon ligand binding, transmembrane cytokine receptors multimerize, bringing receptor-associated JAKs into close physical proximity. Once activated via transphosphorylation, JAKs phosphorylate the cytoplasmic domain of the receptor to provide a docking site for STAT. The bound STATs are then phosphorylated and activated by JAKs. Activated STATs dimerize and translocate into the nucleus where act as transcription factors. Suppressors of cytokine signaling (SOCS) family of proteins inhibit JAK activation; cytokine-inducible SH2-containing protein (CIS) blocks the STAT docking site on the receptor; Protein inhibitor of activated STAT (PIAS) proteins inhibit STAT binding to promoter regions of target genes; and protein tyrosine phosphatase receptors (PTPRs) dephosphorylate STATs. JAKs: Janus kinases; STAT: signal transducer and activator of transcription
The JAK/STAT signaling pathway is modulated by several negative regulators[
Hyperactivation of STATs, particularly STAT3, has been implicated in many cancers. Upstream JAK2 V617F mutations in myeloproliferative diseases and STAT3 mutations in T-cell large granular lymphocytic leukemia provide mechanisms for STAT3 hyperactivity in hematological malignancies[
In most solid tumors associated with hyperactivation of STAT3, disease development and progression has been attributed to either increased cytokine signaling or inhibition of negative regulators of the JAK/STAT pathway[
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 target in this malignancy[
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.
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.
JAK inhibitors: chemical structures for JAK inhibitors described in this review were created using MarvinSketch software downloaded from ChemAxon (Budapest, Hungary)[
JAK inhibitors tested clinically in solid tumors
Inhibitor | Direct Target(s) | NCT# | Type(s) of solid tumor | Status | Outcome |
---|---|---|---|---|---|
Ruxolitinib* | JAK1/2 | NCT01423604 | PDAC | Completed | Improved overall survival in subgroup of patients with inflammation[ |
NCT02117479 | PDAC | Terminated | No overall survival benefit[ |
||
NCT02119663 | PDAC | Terminated | No overall survival benefit[ |
||
NCT02120417 | BC | Terminated | Favorable HRQoL, no overall survival benefit[ |
||
NCT01562873 | BC | Terminated | No tumor response[ |
||
NCT01594216 | BC | Completed | None published | ||
NCT02119676 | CRC | Terminated | No overall survival benefit[ |
||
NCT02119650 | NSCLC | Terminated | Unable to interpret efficacy[ |
||
NCT02145637 | NSCLC | Completed | 23.3% PR, 70.0% SD[ |
||
NCT02155465 | Lung adenocarcinoma | Completed | Lack of efficacy[ |
||
NCT01822756 | Advanced solid tumors | Terminated | Unable to interpret efficacy[ |
||
NCT00638378 | PC | Terminated | Lack of clinical response | ||
NCT02955940 | PDAC, CRC, BC, NSCLC | Active | |||
NCT03153982 | HNC | Active | |||
NCT02928978 | Premalignant breast disease | Active | |||
NCT03514069 | High-grade gliomas | Active | |||
NCT04303403 | CRC, PDAC | Active | |||
NCT03012230 | BC | Active | |||
NCT02876302 | IBC | Active | |||
NCT02041429 | IBC | Active | |||
NCT02066532 | BC | Active | |||
NCT02713386 | OC, fallopian tube cancer, peritoneal cancer | Active | |||
NCT02788201 | UC | Completed | None published | ||
Tofacitinib* | JAK1 | NCT04034238 | Epithelioid mesothelioma, cholangiocarcinoma, PDAC | Active | |
AZD1480 | JAK1/2 | NCT01112397 | Advanced solid tumors, not specified | Terminated | pSTAT3 inhibition in granulocytes, neurotoxicity in patients[ |
NCT01219543 | HCC, NSCLC, GC | Terminated | None published | ||
AZD4205 | JAK1 | NCT03450330 | NSCLC | Completed | None published |
INCB047986 | JAK1 | NCT01929941 | PDAC, BC, non-specified advanced solid tumors | Terminated | None published |
INCB052793 | JAK1 | NCT02265510 | Non-specified advanced solid tumors | Terminated | Lack of efficacy |
Itacitinib | JAK1 | NCT01858883 | Variety (84% PDAC) | Completed | Lack of efficacy in JANUS 1 and JANUS 2 trials[ |
NCT04358185 | HCC | Active | |||
NCT03425006 | NSCLC | Active | |||
NCT02917993 | NSCLC | Active | |||
NCT02646748 | CRC, endometrial cancer, HNC, lung cancer, BC, PDAC, RCC, UC | Active | |||
NCT03670069 | Soft tissue sarcoma | Suspended | |||
NCT02257619 | NSCLC | Terminated | None published | ||
NCT02559492 | Non-specified advanced solid tumors | Terminated | None published | ||
Momelotinib | JAK1/2
|
NCT02101021 | PDAC | Terminated | No overall survival benefit[ |
NCT02258607 | NSCLC | Terminated | No overall survival benefit[ |
||
NCT02206763 | NSCLC | Terminated | Neutropenia[ |
||
NCT02244489 | PDAC | Terminated | None published | ||
Pacritinib | JAK2 | NCT02277093 | CRC | Terminated | Lack of clinical response |
NCT02342353 | NSCLC | Terminated | None published | ||
WP1066 | JAK2 | NCT04334863 | Medulloblastoma, brain metastases | Active | |
NCT01904123 | Glioma, brain metastases | Active |
This table summarizes active, completed, or terminated clinical trials registered in
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[
Ruxolitinib has also been shown to overcome drug resistance and increase sensitivity to several chemotherapeutic or targeted agents. In preclinical
Several clinical trials have studied the impact of ruxolitinib in patients with solid tumors. In a Phase II study of ruxolitinib and capecitabine in patients with pancreatic cancer who failed to respond to gemcitabine, known as the RECAP trial, there was improved survival among a subgroup of patients with inflammation, defined by a C-reactive protein (CRP) greater than the population median of 13 mg/L (NCT01423604)[
Several ongoing early-stage clinical trials are investigating ruxolitinib as monotherapy. There are two current window-of-opportunity trials: one testing neoadjuvant ruxolitinib in HNC (NCT03153982) and one examining ruxolitinib in premalignant breast disease (NCT02928978). Some trials are also investigating ruxolitinib in combination other agents. Among these are a Phase I study testing ruxolitinib in combination with temozolomide in patients with high-grade gliomas (NCT03514069), a Phase Ib study of ruxolitinib and trametinib (MEK inhibitor) in colon and pancreatic cancers with RAS mutations (NCT04303403), a Phase I study testing ruxolitinib with pembrolizumab (PD-L1 inhibitor) in triple-negative breast cancer (NCT03012230), two Phase II studies investigating ruxolitinib with chemotherapy in inflammatory breast cancer (NCT02876302, NCT02041429), a Phase I/II trial evaluating ruxolitinib with trastuzumab (HER2 inhibitor) in HER2+ breast cancer (NCT02066532), and a Phase I/II study of ruxolitinib with paclitaxel and carboplatin in ovarian, fallopian tube, and peritoneal cancers (NCT02713386). Ruxolitinib is one of 75 approved agents being tested in a trial that uses the Co-eXpression ExtrapolatioN (COXEN) model to identify biomarkers and to predict which drugs would provide the most benefit to patients with urothelial cancer (NCT02788201).
Tofacitinib is a JAK1/3 inhibitor that is FDA approved for treatment of rheumatoid arthritis and ulcerative colitis[
AZD1480 is a selective ATP-competitive JAK1/2 inhibitor that showed promising activity against many solid tumor preclinical models. AZD1480 treatment of cell lines and murine models, including but not limited to GBM[
AZD4205 is a selective JAK1 inhibitor[
INCB047986 and INCB052793 are selective inhibitors of JAK1. INCB047986 was studied in a Phase I clinical trial in breast and pancreatic cancers, among other solid tumors, but the trial was terminated early (NCT01929941). INCB052793 has been studied in multiple myeloma (MM) preclinical models, but there are no reports using this agent in solid tumors. In combination with other anti-MM agents, INCB052793 decreased cell viability and inhibited tumor growth[
Preclinical studies of the JAK1 inhibitor itacitinib have mostly been conducted in preclinical models of hematological malignancies. In conjunction with INCB054329, an inhibitor of bromodomain and extra-terminal motif proteins, itacitinib inhibited STAT3 activation and tumor growth in MM cell lines and murine models[
Momelotinib is a JAK1/2 inhibitor that also has activity against TANK-binding kinase 1 (TBK1)[
Clinical use of momelotinib has been studied extensively in myeloproliferative diseases: in myelofibrosis, treatment with this agent was associated with a reduction in splenic volume that was non-inferior to ruxolitinib[
Pacritinib is a selective JAK2 inhibitor currently being studied in a Phase III clinical trial for treatment of myelofibrosis (NCT02055781)[
WP1066 inhibits JAK2 phosphorylation and causes JAK2 degradation; it is an analog of the JAK2 inhibitor AG490, an agent which was widely tested in preclinical modes of solid tumors[
While several JAK inhibitors have not yet been tested in patients with solid tumors, they have shown promising anti-cancer effects in preclinical models. Agents such as AG490, the compound from which WP1066 was derived, and JAK inhibitor I have been widely tested in preclinical
Fedratinib is an orally bioavailable, small molecule, JAK2 inhibitor that is FDA approved for the treatment of myelofibrosis[
Filgotinib is a selective JAK1 inhibitor currently being investigated in clinical trials for treatment of rheumatoid arthritis and inflammatory bowel disease; to date, this drug demonstrates a significant anti-inflammatory effect, as it reduces levels of cytokines such as IL-6[
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)[
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[
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[
Drafted and edited manuscript, figures, and tables: Qureshy Z, Johnson DE, Grandis JR
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This work was supported by NIH (R35CA231998) (to Grandis JR), (R01DE028289) (to Johnson DE, Grandis JR); and a Yearlong Research Fellowship awarded by the University of California San Francisco School of Medicine (to Qureshy Z).
Johnson DE and Grandis JR are co-inventors of cyclic STAT3 decoy and have financial interests in STAT3 Therapeutics. STAT3 Therapeutics holds an interest in cyclic STAT3 decoy. Qureshy Z declared that there are no conflicts of interest.
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© The Author(s) 2020.