Targeting STAT3 for Cancer Therapy: Focusing on Y705, S727, or Dual Inhibition?
Simple Summary
Abstract
1. Introduction
2. STAT3 Signaling Mechanisms
2.1. Canonical STAT3 Signaling and the Role of Y705 Phosphorylation
2.2. Noncanonical STAT3 Signaling and the Role of S727 Phosphorylation
2.3. Interplay Between pY705 and pS727 in Cancer
3. Clinical Relevance of STAT3 in Cancer and Rational for Therapeutic Development
3.1. STAT3 Hyperactivation in Various Cancers Is Associated with Poor Prognosis
3.2. Rationale for Targeting STAT3 in Cancer
4. Evaluation of STAT3 Inhibitors of Y705 and/or S727 in Clinical Development
5. Comparative Analysis: Targeting Y705 vs. S727 in STAT3 Inhibitor Design
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
CSC | Cancer stem cell |
EGF | Epidermal growth factor |
EMT | Epithelieal-to-mesenchymal transition |
IL-10 | Interleukin-10 |
IL-6 | Interleukin-6 |
JAK | Janus kinase |
MAPK | Mitogen-activated protein kinase |
MitoSTAT3 | Mitochondrial STAT3 |
PROTAC | Proteolysis-targeting chimeras |
ROS | Reactive oxygen species |
S727 | Serine-727 |
Src | Proto-oncogene tyrosine-protein kinase Src |
STAT3 | Signal transducer and activator of transcription 3 |
U-STAT3 | Unphosphorylated STAT3 |
VEGF | Vascular endothelial growth factor |
Y705 | Tyrosine-705 |
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Tumor Type | Reference(s) |
---|---|
Breast cancer | [3,4,11,44,45] |
Triple-negative breast cancer | [30,43] |
Gastric cancer | [18] |
Lung cancer | [46,47] |
Glioblastoma | [48,49,50] |
Hepatocellular carcinoma | [51,52] |
Pancreatic cancer | [53,54] |
Prostate cancer | [55] |
Colorectal cancer | [56] |
Esophageal cancer | [57,58] |
Compound | Target Domain | pY705 | pS727 | Clinical Efficacy | Toxicity | Current Status |
---|---|---|---|---|---|---|
Stattic | SH2 | Yes | Yes | N/A | High | |
Napabucasin (BBI608) | SH2 | Yes | Yes | Low | Low | Phase I/II |
SLSI-1216 | SH2 | Yes | Yes | N/A | N/A | |
C188-9 (TTI-101) | SH2 | Yes | N/A | High | Low | Phase 1/II |
InS3-54 | DNA- binding | No | No | N/A | N/A | |
N4 | SH2 | Yes | No | N/A | Low | |
YY002 | SH2 | Yes | Yes | N/A | Low | |
LLY17 | SH2 | Yes | N/A | N/A | N/A | |
WZ-2-033 | SH2 | Yes | No | N/A | Low | |
OPB-31121 | SH2 | Yes | Yes | Low | High | Phase I |
OPB-51602 | SH2 | Yes | Yes | High | High | Phase I |
VVD-130850 | Allosteric | N/A | N/A | N/A | N/A | |
DCR-STAT3 | RNA | Yes | Yes | N/A | N/A |
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Berkley, K.; Zalejski, J.; Sharma, A. Targeting STAT3 for Cancer Therapy: Focusing on Y705, S727, or Dual Inhibition? Cancers 2025, 17, 755. https://doi.org/10.3390/cancers17050755
Berkley K, Zalejski J, Sharma A. Targeting STAT3 for Cancer Therapy: Focusing on Y705, S727, or Dual Inhibition? Cancers. 2025; 17(5):755. https://doi.org/10.3390/cancers17050755
Chicago/Turabian StyleBerkley, Kyli, Julian Zalejski, and Ashutosh Sharma. 2025. "Targeting STAT3 for Cancer Therapy: Focusing on Y705, S727, or Dual Inhibition?" Cancers 17, no. 5: 755. https://doi.org/10.3390/cancers17050755
APA StyleBerkley, K., Zalejski, J., & Sharma, A. (2025). Targeting STAT3 for Cancer Therapy: Focusing on Y705, S727, or Dual Inhibition? Cancers, 17(5), 755. https://doi.org/10.3390/cancers17050755