STAT3 inhibition, a novel approach to enhancing targeted therapy in human cancers (Review)
- Authors:
- Published online on: July 24, 2012 https://doi.org/10.3892/ijo.2012.1568
- Pages: 1181-1191
Abstract
Contents
Introduction
Biology of STAT3
STAT3 inhibition and preclinical studies
Inhibiting STAT3 in clinical studies
Conclusions
Introduction
Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which in humans is encoded by the STAT3 gene. The protein is a latent cytoplasm transcription factor that relays signals of cytokines and growth factors from the cell membrane to the nucleus to regulate gene expression critical to normal cellular processes, including cell development, differentiation, proliferation, survival, angiogenesis and immune function (1–5). Constitutive STAT3 activation is associated with various human cancers and commonly suggests poor prognosis (6–9). Thus STAT3 has been studied as a tumour therapeutic target. Very recently a tumour suppressor role of STAT3 in a few tumours has also been reported (10,11), but this is not the focus of the present review.
In mammals, the STAT family consists of seven protein members: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6, which are mapped to different human chromosomal regions (12). STAT2, STAT4 and STAT6 are only activated in normal human function, while STAT1, STAT3 and STAT5 play an important role in cancer development (STAT1 as tumour suppressor, STAT3 and STAT5 as oncogenes) (13,14). STAT3 appears to be a critical regulator and is therefore the focus of this review. All of the STAT family comprise 750–850 amino acids and 6 conserved domains: the NH2-terminal, coiled-coil, DNA binding, linker, SH2, and C-terminal transactivation domains (15,16). The C-terminal transactivation domain of STAT3 plays an important role in activation through a tyrosine residue at position 705 and a serine residue at position 727 (17). The SH2 region, a well-characterized small protein module of approximately 100 amino acids (18), is responsible for the binding of STAT3 to the tyrosine-phosphorylated receptors and also the homodimerization or heterodimerizaion of two STAT monomers that is necessary for DNA binding and gene expression (19). SH2 region, NH2-terminal and DNA-binding domain became the targets for development of STAT3 inhibitors.
This review aimed principally to summarise the therapeutic potential of STAT3 inhibitors, specifically STAT3 inhibition and preclinical studies, as well as inhibiting STAT3 in clinical trials.
Biology of STAT3
Normal function of the STAT3 pathways
The STAT3 signalling pathways regulate the gene expression of proliferation, survival, migration and invasion, as well as angiogenesis (2,20) in human. Furthermore, STAT3 is essential at early stages of embryo development (21) and modulates embryonic stem cell differentiation such as TH17 helper T cells (22). In benign cells, the signalling by STAT3 is under tight regulation so that the signal is transient in accordance with physiological responses.
Activation of STAT family and associated pathways
The process of STAT activation commences with the Janus kinases (JAKs) which bind to and are phosphorylated by cytokine or growth factor receptors in response to external signals such as interleukin-6 (IL-6), interferon-α, tumour necrosis factor (TNF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), transforming growth factor-alpha (TGF-α) and TGF-β1 (17,23–25). Subsequently, phosphorylated JAKs in turn cause multiple phosphorylations of tyrosine residues within the cytoplasmic domain of the cytokine receptor (26–28). Monomeric unphosphorylated STAT is recruited to these activated receptors through an interaction between the STAT SH2 domain and phosphotyrosine docking sites on the receptors. JAKs then phosporylate the critical tyrosine on C-terminal domain of STAT, which causes dissociation of STAT from the receptor, this then leads to dimerization of two STAT monomers through reciprocal interaction (2,29,30). Dimeric STAT complexes translocate to the nucleus where they bind to specific DNA response elements in the promoters of target genes (31).
The non-receptor tyrosine kinases such as Src can activate the STAT signalling pathway in the absence of receptor engagement (32–34). In some cases, JAKs as intermediaries are simultaneously involved in activation of STAT by non-receptor tyrosine kinases (35).
Cross-talk with other signalling
In a hepatocellular carcinoma cell (HCC) study, JAK/STAT activated by interferon-α inhibited MAPK signalling by cross-talking with MEK/ERK pathway (36). Our results in sarcoma suggest this may be due to IFNα induced alteration of the balance between STAT1 and STAT3/ STAT5 favouring inhibition of proliferation and subsequent apoptosis (37). Cross-talking among the signalling pathways is complicated and requires further investigations. Increased understanding of cross-talking may provide the rationale for combination therapy using STAT3 inhibitor and other drugs.
Constitutive activation of STAT3 and oncogenesis
Constitutive activation of STAT3 has been reported at high frequency in large numbers of malignant cell lines, in vivo animal experiments and human tumours (35,38,39). Table I includes a broad range of pre-clinical studies, which show that (activated) phosphorylated-STAT3 (pSTAT3) is a common characteristic of many cancers. Constitutive activation of STAT3 involves multiple signalling pathways in both a cell- and tissue-specific manner, making single upstream pathway treatment difficult. So far, there has been no STAT3 gene mutation detected in any cancer. Persistent activation of STAT3 has been attributed to dysregulation of upstream tyrosine kinases and negative regulators in the STAT3 signalling pathway (20,40).
Activated STAT3 regulates many genes whose expression is required in aspects of cancer initiation, development and progression, including uncontrollable proliferation, anti-apoptosis, invasion, angiogenesis and immune surveillance evasion. STAT3 signalling has been implicated in the up-regulation of cell proliferation by cylin D2 and c-Myc (20,34,41–43). In addition, pSTAT3 contributes to malignancy by preventing apoptosis, allowing accumulation of long-lived tumour cells and mediating chemoresistance via increased expression of anti-apoptotic genes such as Bcl-2 family member Bcl-XL and Mcl-2 as well as survivin (43–49). Recently, miRNA-21 has been proved to be STAT3 target gene, which functions as an inhibitor of apoptosis in multiple myeloma and Sézary cells (50,51). Increased VEGF expression in cultured cell lines, animal models and patient cancer specimens, as well as tumour angiogenesis in vivo is also induced via STAT3 pathway in diverse human cancers from head, neck, breast, pancreas, cervix as well as melanoma (27,52-54). Over-expression of matrix metalloproteinase-2 (MMP-2) in melanoma and MMP-9 in breast cancer is attributed to elevated STAT3 activity (55,56). STAT3, which may also be activated in tumour-infiltrating immune cells, can inhibit tumour immune function by promoting the expression of immune suppressive factors and inhibiting the product of pro-inflammatory mediators (39,57–60).
Over-expression of pSTAT3 occurs in a wide range of tumours (25,61,62), suggesting STAT3 may be both a therapeutic target and a clinical prognosticator. Table II outlines clinical studies of pSTAT3 expression in various human tumours. There was a significant correlation between higher pSTAT3 and worse outcomes of tumours, such as breast cancers exhibiting invasiveness, head and neck as well as gastric cancers with nodal metastasis and/or in late clinical stage, as well as prostate cancers displaying high Gleason score (25,43,63,64).
The role of STAT3 as a resistance pathway to targeted therapy
As a class the targeted therapies that inhibit specific biologic pathways represent a novel therapeutic strategy either as single agents or in combination with conventional chemotherapeutics in treating a variety of malignancies. However, patient response has been less than expected and early development of resistance has been a major issue (65). The identification of novel alternative signalling pathways represents one resistance mechanism. For example one recent study demonstrated that EGFR and IGFR signal through JAK/STAT pathway, in addition to the two classical pathways of ras-raf-MEK-ERK and PI3K-Akt (66). Indeed STAT3 is a common alternative pathway for many growth promoting factors effectively bypassing a single tyrosine kinase inhibitor acting at an early point in the receptor activation pathway. For example, owing to the high level of IL-6 in NSCLC, EGFR inhibitor was ineffective due to ongoing STAT3 activation (13). STAT3 is a more downstream point of convergence in many ligand/receptor pathways (such as growth factor and cytokine receptors) and non-receptor tyrosine kinase pathways (such as Src) and consequently cross-talk among these signalling pathways may contribute to resistance to EGFR inhibitors. In addition STAT3 acts as a nuclear transcription factor (41) upregulating genes of cell survival and proliferation. Its inhibition represents a promising target for improving targeted cancer treatment in a number of preclinical studies. Furthermore, considering its late position in activation pathways, its inhibition may be less likely to be overcome through an alternative pathway.
STAT3 inhibition and preclinical studies
Since STAT3 is involved in regulating fundamental biological processes and pSTAT3 contributes to malignant transformation and progression, targeting STAT3 signalling appears to be a novel approach to preventing and treating cancers. Several strategies are being developed to target the STAT3 signalling pathway.
Modulating upstream positive or negative regulators
Inhibiting the upstream signals or enhancing negative regulators of STAT3 signalling pathway is one possible strategy.
i) Inhibition of STAT3 signalling via targeting the activation of cytokine and growth factor receptors with monoclonal antibodies or receptor antagonists: for example, the use of IL-6 receptor super-antagonists, such as Sant7, inhibited IL-6-dependent human myeloma cell growth (IC50 = 0.16 nM), as well as induced cell death as a pro-apoptotic factor via STAT3 signalling (67,68).
ii) Inhibition of upstream tyrosine kinases JAK or Src with small molecule inhibitors such as AG490, INCB20, PD180970 and Dasatinib: for example AG490, a JAK2-specific inhibitor, blocked constitutive activation of STAT3 causing a significant reduction of Bcl-XL mRNA expression and induced cell apoptosis in certain human myeloma and prostate cancer cell lines (69). Pan-JAK inhibitor INCB20 was demonstrated to block STAT3 phosphorylation, induce apoptosis and inhibit human multiple myeloma cell growth with an IC50 of less than 1 μM, as well as dramatically delay tumour growth in subcutaneous xenograft model in mice (26). Dasatinib (BMS-354825), which inhibits Src tyrosine kinase activity, has shown an anti-tumour effect on head and neck squamous cell carcinoma and non-small cell lung cancer cells with low IC50 values in vitro (70).
iii) Enhancement of negative regulators: a number of pathways that negatively regulate STAT3 have been identified. These include suppressors of cytokine signalling (SOCS) family proteins which are transcriptionally regulated by activated STAT and form a negative feedback loop to suppress STAT signal by binding to or inhibiting JAKs or by targeting bound proteins to the proteasome degradation pathway. Other negative regulators include: protein inhibitor of activated STAT (PIAS), various tyrosine phosphatises (SHP1, SHP2, CD45), phosphatase and tensin homolog (PTEN), GRIM-19 (gene associated with retinoid IFN induced mortality-19) as well as the ubiquitin-proteasome degradation pathway involved in negative regulation of STAT signalling (71–81). Recently, neurofibromatosis 2 (NF2) tumour suppressor, schwannomin was also demonstrated to inhibit STAT3 phosphorylation (82).
However, although these are all theoretically attractive, any attempt to activate these pathways as a means of downregulating activated STAT3 is problematic owing to redundancy of upstream proteins, meaning that the STAT3 pathway might not be effectively blocked by a single compound. Furthermore, these compounds might inhibit other downstream targets, which the STAT3 signalling are cross-talking with (39,83) and consequently cause undesirable side effects.
RNA interference
Another approach for STAT3 inhibition is to affect translation of STAT3 mRNA by coding RNA interference, such as domain-negative (DN) STAT3 mutants (STAT3β, STAT3D or STAT3F), anti-sense STAT3 oligonucleotides or small interfering RNA (siRNA). Several groups reported that this strategy can inhibit cellular growth and induce apoptosis in multiple human cancer cells in vitro and in vivo, accompanied with down-regulation of STAT3 target genes. Table III lists some RNAs used in preclinical studies, which target STAT3 mRNA.
Recently, microRNAs, small non-coding RNA molecules, which act as post-transcriptional regulators have also become the focus of research on regulation of gene activity. MicroRNA binds to the 3′ untranslated regions (3′ UTRs) of target mRNA in RNA induced silencing complexes (RISC), and negatively regulates gene expression through transcript destabilization and translational attenuation (84). A variety of microRNAs are linked with cancer initiation and development as tumour suppressors or oncogenes (also called oncomirs) (85–90). Several microRNAs can regulate STAT3 protein expression in embryonic development and cellular differentiation (91,92). However, in tumour-related studies, only two microRNAs, mir-17 and mir-let-7a are identified to regulate STAT3 to date (Fig. 1). The Mir-17 family, as a tumour suppressor, directly regulates STAT3 mRNA expression through binding to and silencing STAT3 3′ UTRs in a breast cancer cell line (MDA-MB-231) (91). Mir-let-7a, as an oncogene, indirectly modulates STAT3 phosphorylation in malignant human cholangiocytes (93). Neurofibromatosis 2 (NF2), a negative regulator of STAT3 phosphorylation, is a direct target gene of mir-let-7a. As such, let-7a microRNA contributes to elevated STAT3 phosphorylation. Thus, microRNA (anti-let 7a and Mir-17 mimic) which blocks the oncogene or replace the lost suppressor function have the potential for an anti-tumour effect.
Importantly, such gene therapy displayed anti-tumour bystander effects, in which adjacent tumour cells that did not receive the gene therapy also underwent apoptosis (94,95). For example, gene therapy using STAT3β RNA blockade caused the tumour regression seen with massive apoptosis of both transfected and bystander tumour cells.
However, more new techniques will be needed to overcome the small RNA delivery limitations and subsequent immune response in patients (84,96). Some other major problems of RNA delivery include rapid excretion by kidney, degradation in extracellular fluid and permeability to the cell membrane. Nevertheless, approaches using different delivery agents (liposome, nanoparticle and LNA oligonucleotide) have entered preclinical and phase I clinical trials (97,98).
Targeting STAT3 protein directly
The best approach may be to inhibit STAT3 protein directly. The three domains of STAT3: NH2-terminal, DNA-binding and SH2 were identified as selective targets for development of STAT3 inhibitors based on the understanding of the structure and function of STAT3 (99). The most popular target is the SH2 domain, since it is necessary for STAT3 recruiting to any activated receptor. In addition, inhibition of this target can block STAT3 dimerization and consequently inhibit nuclear translocation and STAT3-dependent gene regulation. So far, three categories of STAT3 SH2 inhibitors have been developed including peptides, peptidomimics and small molecule inhibitors. Several phosphotyrosyl peptides (PpYLKTK), tripeptides (PpYL, ApYL) and peptidomimetics (ISS610) were demonstrated to inhibit STAT3 dimerization, cell proliferation and gene regulation in vitro. PpYLKTK, PpYL and ApYL, which are STAT3 SH2 domain-binding peptides, blocked STAT3 DNA-binding activity with an IC50 of 235, 182 and 217 μM, respectively (100). The most effective yet reported ISS610 disrupted STAT3 dimerization, inhibited cell growth and induced apoptosis, as well as reduced DNA-binding activity with an IC50 of 42 μM in cells with pSTAT3 (101). However, poor cell permeability and in vivo stability is the limitation to applying peptide-based inhibitors to clinical trials (83).
Multiple novel small molecular inhibitors targeting STAT3 SH2 domain were identified and designed through structure-based high-throughout virtual screening and have been demonstrated to inhibit STAT3 dimerization and DNA-binding activity, as well as inhibit cell proliferation and tumour growth in cultured cancer cell lines and in animal models respectively. Table IV summarizes the inhibitors reported to target SH2 domain, as well as the related mechanism studies, including STA-21 and analogue, Stattic, S3I-201 (NSC 74859) and analogue, S3I-M2001, 5,15-DPP, LLL12 and STX-0119. S3I-201 selectively inhibited STAT3 DNA-binding activity, STAT3 dimerization and transcriptional activity, as well as induced growth inhibition and apoptosis in cells with persistent pSTAT3 (102,103). Moreover, in both human breast and hepatocellular cancer xenografts in nude mouse model, S3I-201 significantly inhibited the tumour growth with a dose of 5 mg/kg. OPB-31121, another small molecule inhibitor, inhibits cell proliferation with low IC50 in a number of hematopoietic malignancy cell lines through direct blockage of STAT3 phosphorylation in preclinical studies (104). OPB-31121 has been used in clinical trials and is introduced below in the clinical study section.
Collectively, small molecule inhibitors targeting STAT3 directly are the most promising of the possible therapeutic strategies because: i) modulation of upstream regulators by single targeted therapy may not completely block the STAT3 pathway due to multiple regulators and cross-talking among pathways; ii) RNA inhibition requires yet to be identified improved techniques to deal with the delivery issues; iii) the preclinical studies demonstrate that small molecule inhibitors strongly inhibited the growth both of tumour cells in vitro and xenografts in animal models with a low IC50 encouraging clinical development and reducing the risk of development of resistance.
STAT3 inhibition combined with other targeted therapy or chemotherapy
In addition, synergy may be expected with many other inhibitors, since STAT3 is a complementary pathway for many growth factor pathways. The combination therapy of STAT3 and EGFR inhibitors synergistically and significantly suppressed cancer cell growth and down-regulated activated STAT3 expression in high-grade gliomas and pancreatic cancers (41,105). Furthermore, STAT3 inhibition increased the sensitivity of cancer cells to chemotherapeutic agents such as taxol and cisplatin (105,106). Therefore, STAT3 is an attractive target and some new studies on STAT3 mono-therapy and combination therapy are ongoing.
Inhibiting STAT3 in clinical studies
There are several phase 0/I clinical trials of STAT3 inhibition ongoing or not yet reported (Table V). OPB-31121, which inhibits STAT3 phosphorylation, but did not affect JAK kinase, displayed strong anti-proliferation effect in cancer cell lines and in mouse model in vivo studies (104). Preliminary data are currently only available from one Korean study reported in the Annual Meeting of the American Society of Clinical Oncology (107) in 21 patients with advanced refractory solid tumours treated by OPB-31121. This showed that toxicities were predominantly grade 1 or 2, with the dose-limiting toxicities (DLT) of grade 3 vomiting and diarrhoea. The MTD has not been determined within the designated dose range. Eight out of 17 patients had the stable disease, with one case more than 12 months. It seems that this oral STAT3 inhibitor is safe and tolerable. More data from different clinical trials of different phases using this kind of drug are required before a clear conclusion can be made.
Conclusions
STAT3 play a pivotal role in the initiation, development and progression of cancers, including proliferation, anti-apoptosis, invasion, angiogenesis and immune surveillance evasion. Constitutively activated STAT3 is associated with a wide range of human cancers. As such, STAT3 has been identified as a novel target to treat and prevent cancers with a broad potential application. Several STAT3 inhibitors display anti-tumour effectiveness in preclinical studies. The data for clinical trials using STAT3 inhibitors are emerging. Targeting STAT3 using a specific inhibitor may be a useful cancer treatment approach, with the potential for a broad clinical impact.
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