Understanding STAT3, the intersection of many carcinogenic signaling pathways

Multiple studies have shown STAT3 to be a tumor microenvironment modulator and a cancer driver, making it one of the most alluring targets in oncology and immune-oncology. The production of STAT3 inhibitors is accelerating, and the novel strategy PROTAC has effectively broken the “incurable” impasse of STAT3.

Double certification of scientific research and capital, the next outlet of tumor immunotherapy; what is the basis of STAT3?

A class of cytoplasmic transcription factors known as signal transduction and transcriptional activators (STAT, or signal transducer and activator of transcription) attach to DNA and frequently react to various external cytokine and growth factor signals.

After activation, it moves from the cytoplasm to the nucleus, where it binds to certain locations on the target gene’s promoter sequence. This promotes transcription and helps with key physiological processes, including cell division, apoptosis, proliferation, and differentiation.

The mammalian STAT family primarily consists of the genes STAT1, STAT2, STAT3, STA4, STAT5a, STAT5b, and STAT6. The oncogenic signaling pathways STAT3 and STAT5 converge, have a strong association with tumor growth and are thought to be the next avenue for cancer therapy.

STAT3 signaling pathway

JAK-STAT signal pathways

A crucial signal sensor for numerous cytokines, growth factors, and interferons is JAK (Janus kinase). Some cytokines connect to the appropriate receptors under certain stress response situations, causing Janus kinase to get phosphorylated and STAT3 to become activated. As a transcriptional regulator, the activated STAT3 dimer will subsequently bind to certain DNA sequences.

Currently, it has been established that the most well-known IL6/JAK/STAT3/pathway affects target gene transcription relevant to breast cancer development and induces chemoresistance in breast cancer.

SRC-STAT signal pathways

The constitutive activation of STAT3 can also result from non-receptor tyrosine kinases like SRC and ABL. SRC has the ability to activate STAT3 and cause the phosphorylation of tyrosine residues, which enhances transport to the nucleus and controls gene transcription.

Understanding STAT3, the intersection of many carcinogenic signaling pathways

STAT3 signaling pathway. Image Credit: ACROBiosystems

STAT3 and cancer

According to research, STAT3 has shown to be overexpressed in a wide range of human malignancies and is crucial for the tumor microenvironment’s (TME) signaling transduction as well as the advancement of the disease in the following ways:

  • Promote tumor progression: TME-associated CAFs are activated by STAT3 activation, which increases the production of immunosuppressive substances like IL-6, IL-10, and EGFR. The STAT3 in CAFs promotes stroma remodeling, tumor growth, tumor proliferation, survival, and migration
  • Induce TME Immunosuppressive: As STAT3 levels rise in the TME, immunological checkpoint molecules such as PD-L1, PD-L2, and CTLA-4 are released more often. This results in the enrichment of Treg cells and B cells and the polarization of M2 macrophages, which leads to immune evasion
  • Reduce anti-tumor immunity: The lysis activity of anti-tumor cells is inhibited by increased STAT3 in CD8+ T cells, NK cells, and neutrophils. By preventing the maturation, activation, and antigen delivery of dendritic cells, STAT3 can also undermine their capacity to fight tumors

Understanding STAT3, the intersection of many carcinogenic signaling pathways

The mechanism of action of STAT3 in TME. Image Credit: ACROBiosystems

Targeted STAT3 drug development

Multiple studies have shown STAT3 to be a tumor microenvironment modulator and a cancer driver, making it one of the most intriguing targets in oncology and immune-oncology.

STAT3 inhibitors

Currently, STAT3 small molecule inhibitors can directly block STAT3 by preventing STAT3 from being phosphorylated and preventing the synthesis of useful STAT3 dimers. Additionally, certain inhibitors disrupt upstream signal pathways, including EGF, VEGF, JAK, etc., to indirectly decrease STAT3.

Combined therapy

Combined immunotherapy that targets STAT3 is believed to increase anti-tumor activity while simultaneously lowering tumor resistance. Additionally, STAT3 inhibitors and CAR-T cells together can lessen CAR-T cell overexpansion, treat cytokine release syndrome (CRS), and lower the frequency of immune-related adverse effects.

Understanding STAT3, the intersection of many carcinogenic signaling pathways

Targets STAT3 inhibitors and combination immunotherapy. Image Credit: ACROBiosystems

PROTAC

PROTAC has great drug effectiveness and higher selectivity due to its capacity to inhibit the target protein’s activity and block the target protein’s expression, which makes it a novel way in which to break the non-druggable nature of STAT3.

On June 2nd, 2022, Kymera Therapeutics said that the FDA has given KT-333, a STAT3 protein-degrading agent, orphan drug status for the treatment of peripheral T-cell lymphoma (PTCL).

Understanding STAT3, the intersection of many carcinogenic signaling pathways

Image Credit: ACROBiosystems

Conclusion

Multiple studies have shown that STAT3 is overactivated in a variety of human malignancies and functions as a tumor microenvironment regulator and cancer driver, making it one of the most appealing targets in oncology and immuno-oncology.

Several STAT3 inhibitors have undergone clinical trials, and several have had impressive effects in vitro and in vivo. PROTAC has also overcome the impasse in achieving orphan drug classification and can be utilized as a new concept for the creation of potent STAT3 inhibitors.

With expanding research, the creation of STAT3-targeting medications in the future can be anticipated.

The whole range of solutions offered by ACROBiosystems is intended to facilitate the development of STAT3-targeted medicines by offering a comprehensive in vitro validation methodology from binding to functional assay.

Target protein

  • Can be used in the study of the STAT3 signaling pathway and the development of STAT3-targeted drugs
  • The binding activity with degrader was confirmed by BLI and SPR
  • Cover both internal and external targets of the STAT3 classical signaling pathway, including EGF、EGF R、IL-6、IL-6 R alpha、JAK1、STAT3, etc
  • Over 90% purity verified by SDS-PAGE and MALS

Product list

Click on the molecule to view the product details

Source: ACROBiosystems

 
STAT3 JAK1
IL-6 IL-6 R alpha
EGF EGF R

 

Validation system

Understanding STAT3, the intersection of many carcinogenic signaling pathways

The purity of Human STAT3, His Tag (Cat. No. ST3-H5149) is more than 95% verified by SDS-PAG and greater than 90% verified by SEC-MALS. The molecular weight of this protein is around 60–75 kDa. Image Credit: ACROBiosystems

Understanding STAT3, the intersection of many carcinogenic signaling pathways

Human STAT3, His Tag (Cat. No. ST3-H5149) immobilized on CM5 Chip can bind STAT3 inhibitor with an affinity constant of 44.6 nM as determined in a SPR assay (Biacore 8K) (QC tested). Image Credit: ACROBiosystems

Reporting gene cell line

  • For small molecule inhibitors or antibodies that target the STAT3 signaling pathway development and function verification
  • Large detection window for different drag screening
  • Strong response signal to ensure high sensitivity
  • The reporter gene cell lines were designed based on the MOA of drags
  • Good generation stability, stable for 10-20 generations

Product list

Source: ACROBiosystems

Cat. No. Product Description
CHEK-ATF049 EGFR (Luc) HEK293 Reporter Cell
CHEK-ATF047 STAT3 (Luc) HEK293 Reporter Cell

 

Validation data

Property verification

Understanding STAT3, the intersection of many carcinogenic signaling pathways

Expression analysis of human EGFR on EGFR (Luc) HEK293 Reporter Cell by FACS. Cell surface staining was performed on EGFR (Luc) HEK293 Reporter Cell or negative control cell using PE-labeled anti-EGFR antibody. Image Credit: ACROBiosystems

Understanding STAT3, the intersection of many carcinogenic signaling pathways

Response to human EGF protein (RLU). The EGFR (Luc) HEK293 Reporter Cell was stimulated with serial dilutions of human EGF protein (Cat. No. EGF-H52H3). The EC50 was approximately 56.23 ng/mL. Image Credit: ACROBiosystems

Understanding STAT3, the intersection of many carcinogenic signaling pathways

Response to human EGF protein (Fold). The EGFR (Luc) HEK293 Reporter Cell was stimulated with serial dilutions of human EGF protein (Cat. No. EGF-H52H3). The max induction fold was approximately 56. Image Credit: ACROBiosystems

Generation stability verification

Understanding STAT3, the intersection of many carcinogenic signaling pathways

Passage stability analysis of receptor expression by FACS. Flow cytometry surface staining of human EGFR on EGFR (Luc) HEK293 Reporter Cell demonstrates consistent mean fluorescent intensity across passage10–20. Image Credit: ACROBiosystems

Understanding STAT3, the intersection of many carcinogenic signaling pathways

Passage stability analysis by Signaling Bioassay. The continuously growing EGFR (Luc) HEK293 Reporter Cell was stimulated with serial dilutions of human EGF protein. Human EGF protein stimulated response demonstrates passage stabilization (fold induction and EC50) across passage 10–20. Image Credit: ACROBiosystems

Pre-coupled magnetic beads

  • It is suitable for high-throughput drug screening
  • The magnetic beads are uniform in diameter, have a large specific surface area, excellent repeatability, and high capture efficiency
  • To guarantee appropriate coating, use the biotin-streptavidin method with saturated concentration antigens

Product list

Source: ACROBiosystems

Cat. No. Product Description
MBE-K012 Monoclonal   Anti-TNF-alpha antibody, Mouse IgG1 (13B8)

 

References

  1. Wingelhofer, B., et al. (2018). Implications of STAT3 and STAT5 signaling on gene regulation and chromatin remodeling in hematopoietic cancer. Leukemia. doi:10.1038/s41375-018-0117-x
  2. Zou, S., et al. (2020). Targeting STAT3 in Cancer Immunotherapy. Molecular Cancer. doi:10.1186/s12943-020-01258-7
  3. He, M., et al. (2022). PROTACs: great opportunities for academia and industry (an update from 2020 to 2021). Signal Transduction and Targeted Therapy. doi:10.1038/s41392-022-00999-9
  4. Radi, G., et al. (2021). The First Jak Inhibitor Approved in Europe for the Treatment of Moderate to Severe Atopic Dermatitis in Adult Patients. Healthcare (Basel). doi:10.3390/healthcare9111575

About ACROBiosystems

ACROBiosystems is a leading manufacturer of recombinant proteins and other critical reagents to support the development of target therapeutics. The company employs an application-oriented development strategy, with a particular focus on product design, quality control, and solution-based support. Our products and services enable anyone in the field of drug development to have a more intuitive and streamlined process.

To respond to the coronavirus pandemic, ACROBiosystems has developed SARS-CoV-2 antigens specifically designed and optimized for serological test kits, including Spike-derived antigen S1, RBD, and Nucleocapsid protein. Proteins have been supplied to diagnostic companies in large quantities.


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Last updated: Aug 2, 2022 at 6:52 AM

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