Oncogenic STAT Transcription Factors as Targets for Cancer Therapy: Innovative Strategies and Clinical Translation
Abstract
:Simple Summary
Abstract
1. Introduction: STAT Transcription Factors
2. Inappropriate Activation of STATs in Cancer
2.1. STAT3
Gene | Function | Status | Cell Source | References |
---|---|---|---|---|
AKT1 | Proliferation | Upregulated | Various human cancer cells | [59] |
BATF | Differentiation | Upregulated | Human Th17 cells | [60] |
Bcl-xL | Anti-apoptosis | Upregulated | Human U266 cells | [14] |
BCL6 | Proliferation | Upregulated | Human Th17 cells | [60] |
MYC | Proliferation | Upregulated | Murine Ba/F3 cells | [61] |
CCND1 | Proliferation | Upregulated | Human gastric cancer cells | [62] |
CDKN2C | Cell cycle inhibition | Downregulated | Human Th17 cells | [60] |
CREM | Spermatogenesis | Downregulated | Human Th17 cells | [60] |
CXCL10 | Angiogenesis, Immune escape | Downregulated | Human CD8+ T cells | [63] |
FOSL2 | Differentiation | Upregulated | Human Th17 cells | [60] |
IKZF2 | Lymphocyte development | Downregulated | Human Th17 cells | [60] |
IL6 | Immune escape | Upregulated | Murine melanoma cells | [64] |
IL10 | Immune escape | Upregulated | Human colon Carcinoma | [65] |
MMP2 | Immune escape | Upregulated | Murine melanoma cells | [66] |
MMP9 | Immune escape | Upregulated | Murine fibroblasts | [67] |
CCL5 | Immune escape | Downregulated | Murine melanoma cells | [64] |
RBPJ | Differentiation | Upregulated | Human Th17 cells | [60] |
SMAD7 | Differentiation | Downregulated | Human Th17 cells | [60] |
STAT1 | Differentiation | Downregulated | Human Th17 cells | [60] |
STAT2 | Antiviral activity | Downregulated | Human Th17 cells | [60] |
STAT3 | Differentiation | Upregulated | Human Th17 cells | [60] |
TWIST | Immune escape | Upregulated | Human breast carcinomas | [68] |
VEGF | Angiogenesis, immune escape | Upregulated | Murine fibroblasts | [67] |
VIM | Immune escape | Upregulated | Monkey kidney cells | [69] |
2.2. STAT5
Gene | Function | Status | Cell Source | References |
---|---|---|---|---|
ARNT | Protein sumoylation | Downregulated | Mouse proB cells | [84] |
BCL2 | Anti-apoptosis | Upregulated | Human T cells | [95] |
BCL2L1 | Apoptosis | Upregulated | Mouse proB cells | [84] |
BCLXL | Anti-apoptosis | Upregulated | Human T cells | [95] |
C3AR1 | Chemotaxis | Upregulated | Murine proB cells | [78] |
CISH | STAT inhibitor | Upregulated | Human T cells | [95] |
DUSP1 | Anti-inflammation | Upregulated | Murine proB cells | [78] |
DUSP5 | Anti-proliferation | No change | Human T cells | [95] |
GTF2H5 | DNA repair | Downregulated | Human T cells | [95] |
MBP | Inflammation | No change | Human T cells | [95] |
MYC | Proliferation | Upregulated | Murine proB cells | [78] |
OSM1 | Metabolic process | Upregulated | Human T cells | [95] |
PIM1 | Proliferation, survival | Upregulated | Human T cells | [95] |
PIM2 | Cell survival | Upregulated | Murine proB cells | [78] |
RO60 | Sperm antigen | Downregulated | Mouse proB cells | [84] |
RK | Proliferation | Upregulated | Murine proB cells | [78] |
SERPINA3G | Proliferation | Upregulated | Murine proB cells | [78] |
SGK1 | Proliferation | Downregulated | Human T cells | [95] |
SLC22A5 | Carnitine uptake | Downregulated | Human T cells | [95] |
SOCS1 | Apoptosis | Upregulated | Murine proB cells | [78] |
SOCS2 | inflammation | Upregulated | Human T cells | [95] |
SRP9 | RNA binding | Upregulated | Mouse proB cells | [84] |
TNFRSf13B | B cell homeostasis | Upregulated | Murine proB cells | [78] |
2.3. Other STATs
3. Targeting STATs for Cancer Therapy
4. Strategies to Directly Target STATs
4.1. Direct STAT Binding Molecules
4.2. STAT Degraders
5. Targeting Upstream Kinases: STAT Phosphorylation as a Biomarker for On-Target Effects
5.1. Inhibiting STAT5 in Chronic Myeloid Leukemia
5.2. Targeting Kinases Upstream of STATs in AML
6. Novel Ways to Identify STAT Transcriptional Inhibitors
6.1. Chemical Biology Approaches
6.2. Computational Approaches Leveraging Transcriptional Signatures
7. Conclusions and Future Directions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Global Cancer Facts & Figures. Available online: https://www.cancer.org/research/cancer-facts-statistics/global.html (accessed on 24 August 2023).
- Sadowski, H.B.; Shuai, K.; Darnell, J.E.; Gilman, M.Z. A common nuclear signal transduction pathway activated by growth factor and cytokine receptors. Science 1993, 261, 1739–1744. [Google Scholar] [CrossRef]
- Wegenka, U.M.; Lütticken, C.; Buschmann, J.; Yuan, J.; Lottspeich, F.; Müller-Esterl, W.; Schindler, C.; Roeb, E.; Heinrich, P.C.; Horn, F. The interleukin-6-activated acute-phase response factor is antigenically and functionally related to members of the signal transducer and activator of transcription (STAT) family. Mol. Cell. Biol. 1994, 14, 3186–3196. [Google Scholar] [CrossRef]
- Darnell, J.E.; Kerr, I.M.; Stark, G.R. Jak-STAT Pathways and Transcriptional Activation in Response to IFNs and Other Extracellular Signaling Proteins. Science 1994, 264, 1415–1421. [Google Scholar] [CrossRef]
- Orlova, A.; Wagner, C.; de Araujo, E.D.; Bajusz, D.; Neubauer, H.A.; Herling, M.; Gunning, P.T.; Keserű, G.M.; Moriggl, R. Direct Targeting Options for STAT3 and STAT5 in Cancer. Cancers 2019, 11, 1930. [Google Scholar] [CrossRef]
- Wang, W.; Lopez McDonald, M.C.; Kim, C.; Ma, M.; Pan, Z.T.; Kaufmann, C.; Frank, D.A. The complementary roles of STAT3 and STAT1 in cancer biology: Insights into tumor pathogenesis and therapeutic strategies. Front. Immunol. 2023, 14, 1265818. [Google Scholar] [CrossRef]
- Mitchell, T.J.; John, S. Signal transducer and activator of transcription (STAT) signalling and T-cell lymphomas. Immunology 2005, 114, 301–312. [Google Scholar] [CrossRef]
- Yoshimura, A.; Naka, T.; Kubo, M. SOCS proteins, cytokine signalling and immune regulation. Nat. Rev. Immunol. 2007, 7, 454–465. [Google Scholar] [CrossRef]
- Chung, C.D.; Liao, J.; Liu, B.; Rao, X.; Jay, P.; Berta, P.; Shuai, K. Specific Inhibition of Stat3 Signal Transduction by PIAS3. Science 1997, 278, 1803–1805. [Google Scholar] [CrossRef]
- Heppler, L.N.; Frank, D.A. Rare mutations provide unique insight into oncogenic potential of STAT transcription factors. J. Clin. Investig. 2018, 128, 113–115. [Google Scholar] [CrossRef]
- Bar-Natan, M.; Nelson, E.A.; Xiang, M.; Frank, D.A. STAT signaling in the pathogenesis and treatment of myeloid malignancies. JAK-STAT 2012, 1, 55–64. [Google Scholar] [CrossRef]
- Frank, D.A. STAT signaling in the pathogenesis and treatment of cancer. Mol. Med. Camb. Mass 1999, 5, 432–456. [Google Scholar] [CrossRef]
- Boudny, V.; Kovarik, J. JAK/STAT signaling pathways and cancer. Janus kinases/signal transducers and activators of transcription. Neoplasma 2002, 49, 349–355. [Google Scholar]
- Catlett-Falcone, R.; Landowski, T.H.; Oshiro, M.M.; Turkson, J.; Levitzki, A.; Savino, R.; Ciliberto, G.; Moscinski, L.; Fernández-Luna, J.L.; Nuñez, G.; et al. Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity 1999, 10, 105–115. [Google Scholar] [CrossRef]
- Bromberg, J.F.; Wrzeszczynska, M.H.; Devgan, G.; Zhao, Y.; Pestell, R.G.; Albanese, C.; Darnell, J.E. Stat3 as an Oncogene. Cell 1999, 98, 295–303. [Google Scholar] [CrossRef]
- Sajjad, H.; Imtiaz, S.; Noor, T.; Siddiqui, Y.H.; Sajjad, A.; Zia, M. Cancer models in preclinical research: A chronicle review of advancement in effective cancer research. Anim. Models Exp. Med. 2021, 4, 87–103. [Google Scholar] [CrossRef]
- Miserocchi, G.; Bocchini, M.; Cortesi, M.; Arienti, C.; De Vita, A.; Liverani, C.; Mercatali, L.; Bravaccini, S.; Ulivi, P.; Zanoni, M. Combining preclinical tools and models to unravel tumor complexity: Jump into the next dimension. Front. Immunol. 2023, 14, 1171141. [Google Scholar] [CrossRef] [PubMed]
- Richmond, A.; Su, Y. Mouse xenograft models vs. GEM models for human cancer therapeutics. Dis. Model. Mech. 2008, 1, 78–82. [Google Scholar] [CrossRef]
- Lee, H.; Jeong, A.J.; Ye, S.-K. Highlighted STAT3 as a potential drug target for cancer therapy. BMB Rep. 2019, 52, 415–423. [Google Scholar] [CrossRef] [PubMed]
- Xia, T.; Zhang, M.; Lei, W.; Yang, R.; Fu, S.; Fan, Z.; Yang, Y.; Zhang, T. Advances in the role of STAT3 in macrophage polarization. Front. Immunol. 2023, 14, 1160719. [Google Scholar] [CrossRef]
- Grandis, J.R.; Drenning, S.D.; Zeng, Q.; Watkins, S.C.; Melhem, M.F.; Endo, S.; Johnson, D.E.; Huang, L.; He, Y.; Kim, J.D. Constitutive activation of Stat3 signaling abrogates apoptosis in squamous cell carcinogenesis in vivo. Proc. Natl. Acad. Sci. USA 2000, 97, 4227–4232. [Google Scholar] [CrossRef]
- Bromberg, J. Stat proteins and oncogenesis. J. Clin. Investig. 2002, 109, 1139–1142. [Google Scholar] [CrossRef]
- Lee, H.; Herrmann, A.; Deng, J.-H.; Kujawski, M.; Niu, G.; Li, Z.; Forman, S.; Jove, R.; Pardoll, D.M.; Yu, H. Persistently Activated Stat3 Maintains Constitutive NF-κB Activity in Tumors. Cancer Cell 2009, 15, 283–293. [Google Scholar] [CrossRef] [PubMed]
- Berthenet, K.; Bokhari, A.; Lagrange, A.; Marcion, G.; Boudesco, C.; Causse, S.; De Thonel, A.; Svrcek, M.; Goloudina, A.R.; Dumont, S.; et al. HSP110 promotes colorectal cancer growth through STAT3 activation. Oncogene 2017, 36, 2328–2336. [Google Scholar] [CrossRef] [PubMed]
- Hsu, K.-W.; Hsieh, R.-H.; Huang, K.-H.; Fen-Yau Li, A.; Chi, C.-W.; Wang, T.-Y.; Tseng, M.-J.; Wu, K.-J.; Yeh, T.-S. Activation of the Notch1/STAT3/Twist signaling axis promotes gastric cancer progression. Carcinogenesis 2012, 33, 1459–1467. [Google Scholar] [CrossRef] [PubMed]
- Niwa, Y.; Kanda, H.; Shikauchi, Y.; Saiura, A.; Matsubara, K.; Kitagawa, T.; Yamamoto, J.; Kubo, T.; Yoshikawa, H. Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma. Oncogene 2005, 24, 6406–6417. [Google Scholar] [CrossRef] [PubMed]
- Isomoto, H.; Mott, J.L.; Kobayashi, S.; Werneburg, N.W.; Bronk, S.F.; Haan, S.; Gores, G.J. Sustained IL-6/STAT-3 signaling in cholangiocarcinoma cells due to SOCS-3 epigenetic silencing. Gastroenterology 2007, 132, 384–396. [Google Scholar] [CrossRef] [PubMed]
- Ogata, H.; Chinen, T.; Yoshida, T.; Kinjyo, I.; Takaesu, G.; Shiraishi, H.; Iida, M.; Kobayashi, T.; Yoshimura, A. Loss of SOCS3 in the liver promotes fibrosis by enhancing STAT3-mediated TGF-beta1 production. Oncogene 2006, 25, 2520–2530. [Google Scholar] [CrossRef] [PubMed]
- Kamran, M.Z.; Patil, P.; Gude, R.P. Role of STAT3 in Cancer Metastasis and Translational Advances. BioMed Res. Int. 2013, 2013, 421821. [Google Scholar] [CrossRef] [PubMed]
- Tolomeo, M.; Cascio, A. The Multifaced Role of STAT3 in Cancer and Its Implication for Anticancer Therapy. Int. J. Mol. Sci. 2021, 22, 603. [Google Scholar] [CrossRef]
- Lin, L.; Liu, A.; Peng, Z.; Lin, H.-J.; Li, P.-K.; Li, C.; Lin, J. STAT3 is necessary for proliferation and survival in colon cancer-initiating cells. Cancer Res. 2011, 71, 7226–7237. [Google Scholar] [CrossRef]
- Niu, G.; Wright, K.L.; Huang, M.; Song, L.; Haura, E.; Turkson, J.; Zhang, S.; Wang, T.; Sinibaldi, D.; Coppola, D.; et al. Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 2002, 21, 2000–2008. [Google Scholar] [CrossRef]
- Priego, N.; Zhu, L.; Monteiro, C.; Mulders, M.; Wasilewski, D.; Bindeman, W.; Doglio, L.; Martínez, L.; Martínez-Saez, E.; Ramón, Y.; et al. STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis. Nat. Med. 2018, 24, 1024–1035. [Google Scholar] [CrossRef]
- Garcia, R.; Bowman, T.L.; Niu, G.; Yu, H.; Minton, S.; Muro-Cacho, C.A.; Cox, C.E.; Falcone, R.; Fairclough, R.; Parsons, S.; et al. Constitutive activation of Stat3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells. Oncogene 2001, 20, 2499–2513. [Google Scholar] [CrossRef]
- Alvarez, J.V.; Mukherjee, N.; Chakravarti, A.; Robe, P.; Zhai, G.; Chakladar, A.; Loeffler, J.; Black, P.; Frank, D.A. A STAT3 Gene Expression Signature in Gliomas is Associated with a Poor Prognosis. Transl. Oncogenom. 2007, 2, 99–105. [Google Scholar] [CrossRef]
- Carpenter, R.L.; Lo, H.-W. STAT3 Target Genes Relevant to Human Cancers. Cancers 2014, 6, 897–925. [Google Scholar] [CrossRef]
- Swerdlow, S.H.; Campo, E.; Pileri, S.A.; Harris, N.L.; Stein, H.; Siebert, R.; Advani, R.; Ghielmini, M.; Salles, G.A.; Zelenetz, A.D.; et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016, 127, 2375–2390. [Google Scholar] [CrossRef]
- Moignet, A.; Lamy, T. Latest Advances in the Diagnosis and Treatment of Large Granular Lymphocytic Leukemia. Am. Soc. Clin. Oncol. Educ. Book Am. Soc. Clin. Oncol. Annu. Meet. 2018, 38, 616–625. [Google Scholar] [CrossRef] [PubMed]
- Lamy, T.; Moignet, A.; Loughran, T.P. LGL leukemia: From pathogenesis to treatment. Blood 2017, 129, 1082–1094. [Google Scholar] [CrossRef]
- Fasan, A.; Kern, W.; Grossmann, V.; Haferlach, C.; Haferlach, T.; Schnittger, S. STAT3 mutations are highly specific for large granular lymphocytic leukemia. Leukemia 2013, 27, 1598–1600. [Google Scholar] [CrossRef] [PubMed]
- Koskela, H.L.M.; Eldfors, S.; Ellonen, P.; van Adrichem, A.J.; Kuusanmäki, H.; Andersson, E.I.; Lagström, S.; Clemente, M.J.; Olson, T.; Jalkanen, S.E.; et al. Somatic STAT3 Mutations in Large Granular Lymphocytic Leukemia. N. Engl. J. Med. 2012, 366, 1905–1913. [Google Scholar] [CrossRef] [PubMed]
- Andersson, E.; Kuusanmäki, H.; Bortoluzzi, S.; Lagström, S.; Parsons, A.; Rajala, H.; van Adrichem, A.; Eldfors, S.; Olson, T.; Clemente, M.J.; et al. Activating somatic mutations outside the SH2-domain of STAT3 in LGL-Leukemia. Leukemia 2016, 30, 1204–1208. [Google Scholar] [CrossRef] [PubMed]
- Semenzato, G.; Teramo, A.; Calabretto, G.; Gasparini, V.R.; Zambello, R. All that glitters is not LGL Leukemia. Leukemia 2022, 36, 2551–2557. [Google Scholar] [CrossRef] [PubMed]
- Dutta, A.; Yan, D.; Hutchison, R.E.; Mohi, G. STAT3 mutations are not sufficient to induce large granular lymphocytic leukaemia in mice. Br. J. Haematol. 2018, 180, 911–915. [Google Scholar] [CrossRef] [PubMed]
- Teramo, A.; Barilà, G.; Calabretto, G.; Ercolin, C.; Lamy, T.; Moignet, A.; Roussel, M.; Pastoret, C.; Leoncin, M.; Gattazzo, C.; et al. STAT3 mutation impacts biological and clinical features of T-LGL leukemia. Oncotarget 2017, 8, 61876–61889. [Google Scholar] [CrossRef] [PubMed]
- Loughran, T.P.; Zickl, L.; Olson, T.L.; Wang, V.; Zhang, D.; Rajala, H.L.M.; Hasanali, Z.; Bennett, J.M.; Lazarus, H.M.; Litzow, M.R.; et al. Immunosuppressive therapy of LGL leukemia: Prospective multicenter phase II study by the Eastern Cooperative Oncology Group (E5998). Leukemia 2015, 29, 886–894. [Google Scholar] [CrossRef]
- Masle-Farquhar, E.; Jackson, K.J.L.; Peters, T.J.; Al-Eryani, G.; Singh, M.; Payne, K.J.; Rao, G.; Avery, D.T.; Apps, G.; Kingham, J.; et al. STAT3 gain-of-function mutations connect leukemia with autoimmune disease by pathological NKG2Dhi CD8+ T cell dysregulation and accumulation. Immunity 2022, 55, 2386–2404.e8. [Google Scholar] [CrossRef] [PubMed]
- Grivennikov, S.; Karin, E.; Terzic, J.; Mucida, D.; Yu, G.-Y.; Vallabhapurapu, S.; Scheller, J.; Rose-John, S.; Cheroutre, H.; Eckmann, L.; et al. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 2009, 15, 103–113. [Google Scholar] [CrossRef] [PubMed]
- Kitamura, H.; Ohno, Y.; Toyoshima, Y.; Ohtake, J.; Homma, S.; Kawamura, H.; Takahashi, N.; Taketomi, A. Interleukin-6/STAT3 signaling as a promising target to improve the efficacy of cancer immunotherapy. Cancer Sci. 2017, 108, 1947–1952. [Google Scholar] [CrossRef] [PubMed]
- Cheng, F.; Wang, H.-W.; Cuenca, A.; Huang, M.; Ghansah, T.; Brayer, J.; Kerr, W.G.; Takeda, K.; Akira, S.; Schoenberger, S.P.; et al. A critical role for Stat3 signaling in immune tolerance. Immunity 2003, 19, 425–436. [Google Scholar] [CrossRef]
- McLemore, M.L.; Grewal, S.; Liu, F.; Archambault, A.; Poursine-Laurent, J.; Haug, J.; Link, D.C. STAT-3 activation is required for normal G-CSF-dependent proliferation and granulocytic differentiation. Immunity 2001, 14, 193–204. [Google Scholar] [CrossRef]
- Zhang, H.; Nguyen-Jackson, H.; Panopoulos, A.D.; Li, H.S.; Murray, P.J.; Watowich, S.S. STAT3 controls myeloid progenitor growth during emergency granulopoiesis. Blood 2010, 116, 2462–2471. [Google Scholar] [CrossRef] [PubMed]
- Lee, C.; Raz, R.; Gimeno, R.; Gertner, R.; Wistinghausen, B.; Takeshita, K.; DePinho, R.A.; Levy, D.E. STAT3 is a negative regulator of granulopoiesis but is not required for G-CSF-dependent differentiation. Immunity 2002, 17, 63–72. [Google Scholar] [CrossRef] [PubMed]
- Chou, W.-C.; Levy, D.E.; Lee, C.-K. STAT3 positively regulates an early step in B-cell development. Blood 2006, 108, 3005–3011. [Google Scholar] [CrossRef] [PubMed]
- Diehl, S.A.; Schmidlin, H.; Nagasawa, M.; Blom, B.; Spits, H. IL-6 triggers IL-21 production by human CD4+ T cells to drive STAT3-dependent plasma cell differentiation in B cells. Immunol. Cell Biol. 2012, 90, 802–811. [Google Scholar] [CrossRef] [PubMed]
- Durant, L.; Watford, W.T.; Ramos, H.L.; Laurence, A.; Vahedi, G.; Wei, L.; Takahashi, H.; Sun, H.-W.; Kanno, Y.; Powrie, F.; et al. Diverse targets of the transcription factor STAT3 contribute to T cell pathogenicity and homeostasis. Immunity 2010, 32, 605–615. [Google Scholar] [CrossRef] [PubMed]
- Kaech, S.M.; Cui, W. Transcriptional control of effector and memory CD8+ T cell differentiation. Nat. Rev. Immunol. 2012, 12, 749–761. [Google Scholar] [CrossRef] [PubMed]
- Fu, X.Y. STAT3 in immune responses and inflammatory bowel diseases. Cell Res. 2006, 16, 214–219. [Google Scholar] [CrossRef]
- Xu, Q.; Briggs, J.; Park, S.; Niu, G.; Kortylewski, M.; Zhang, S.; Gritsko, T.; Turkson, J.; Kay, H.; Semenza, G.L.; et al. Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways. Oncogene 2005, 24, 5552–5560. [Google Scholar] [CrossRef]
- Tripathi, S.K.; Chen, Z.; Larjo, A.; Kanduri, K.; Nousiainen, K.; Äijo, T.; Ricaño-Ponce, I.; Hrdlickova, B.; Tuomela, S.; Laajala, E.; et al. Genome-wide Analysis of STAT3-Mediated Transcription during Early Human Th17 Cell Differentiation. Cell Rep. 2017, 19, 1888–1901. [Google Scholar] [CrossRef]
- Odajima, J.; Matsumura, I.; Sonoyama, J.; Daino, H.; Kawasaki, A.; Tanaka, H.; Inohara, N.; Kitamura, T.; Downward, J.; Nakajima, K.; et al. Full oncogenic activities of v-Src are mediated by multiple signaling pathways. Ras as an essential mediator for cell survival. J. Biol. Chem. 2000, 275, 24096–24105. [Google Scholar] [CrossRef]
- Luo, J.; Yan, R.; He, X.; He, J. Constitutive activation of STAT3 and cyclin D1 overexpression contribute to proliferation, migration and invasion in gastric cancer cells. Am. J. Transl. Res. 2017, 9, 5671–5677. [Google Scholar]
- Yue, C.; Shen, S.; Deng, J.; Priceman, S.J.; Li, W.; Huang, A.; Yu, H. STAT3 in CD8+ T Cells Inhibits Their Tumor Accumulation by Downregulating CXCR3/CXCL10 Axis. Cancer Immunol. Res. 2015, 3, 864–870. [Google Scholar] [CrossRef]
- Wang, T.; Niu, G.; Kortylewski, M.; Burdelya, L.; Shain, K.; Zhang, S.; Bhattacharya, R.; Gabrilovich, D.; Heller, R.; Coppola, D.; et al. Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat. Med. 2004, 10, 48–54. [Google Scholar] [CrossRef]
- Herbeuval, J.-P.; Lelievre, E.; Lambert, C.; Dy, M.; Genin, C. Recruitment of STAT3 for production of IL-10 by colon carcinoma cells induced by macrophage-derived IL-6. J. Immunol. Baltim. Md 1950 2004, 172, 4630–4636. [Google Scholar] [CrossRef]
- Xie, T.-X.; Wei, D.; Liu, M.; Gao, A.C.; Ali-Osman, F.; Sawaya, R.; Huang, S. Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis. Oncogene 2004, 23, 3550–3560. [Google Scholar] [CrossRef]
- Dechow, T.N.; Pedranzini, L.; Leitch, A.; Leslie, K.; Gerald, W.L.; Linkov, I.; Bromberg, J.F. Requirement of matrix metalloproteinase-9 for the transformation of human mammary epithelial cells by Stat3-C. Proc. Natl. Acad. Sci. USA 2004, 101, 10602–10607. [Google Scholar] [CrossRef]
- Lo, H.-W.; Hsu, S.-C.; Xia, W.; Cao, X.; Shih, J.-Y.; Wei, Y.; Abbruzzese, J.L.; Hortobagyi, G.N.; Hung, M.-C. Epidermal growth factor receptor cooperates with signal transducer and activator of transcription 3 to induce epithelial-mesenchymal transition in cancer cells via up-regulation of TWIST gene expression. Cancer Res. 2007, 67, 9066–9076. [Google Scholar] [CrossRef]
- Wu, Y.; Diab, I.; Zhang, X.; Izmailova, E.S.; Zehner, Z.E. Stat3 enhances vimentin gene expression by binding to the antisilencer element and interacting with the repressor protein, ZBP-89. Oncogene 2004, 23, 168–178. [Google Scholar] [CrossRef]
- Wang, Z.; Bunting, K.D. STAT5 in hematopoietic stem cell biology and transplantation. JAK-STAT 2013, 2, e27159. [Google Scholar] [CrossRef] [PubMed]
- Bunting, K.D.; Bradley, H.L.; Hawley, T.S.; Moriggl, R.; Sorrentino, B.P.; Ihle, J.N. Reduced lymphomyeloid repopulating activity from adult bone marrow and fetal liver of mice lacking expression of STAT5. Blood 2002, 99, 479–487. [Google Scholar] [CrossRef] [PubMed]
- Wang, Z.; Li, G.; Tse, W.; Bunting, K.D. Conditional deletion of STAT5 in adult mouse hematopoietic stem cells causes loss of quiescence and permits efficient nonablative stem cell replacement. Blood 2009, 113, 4856–4865. [Google Scholar] [CrossRef]
- Li, G.; Wang, Z.; Miskimen, K.L.; Zhang, Y.; Tse, W.; Bunting, K.D. Gab2 Promotes Hematopoietic Stem Cell Maintenance and Self-Renewal Synergistically with STAT5. PLoS ONE 2010, 5, e9152. [Google Scholar] [CrossRef]
- Lin, J.-X.; Du, N.; Li, P.; Kazemian, M.; Gebregiorgis, T.; Spolski, R.; Leonard, W.J. Critical functions for STAT5 tetramers in the maturation and survival of natural killer cells. Nat. Commun. 2017, 8, 1320. [Google Scholar] [CrossRef]
- Heltemes-Harris, L.M.; Willette, M.J.L.; Ramsey, L.B.; Qiu, Y.H.; Neeley, E.S.; Zhang, N.; Thomas, D.A.; Koeuth, T.; Baechler, E.C.; Kornblau, S.M.; et al. Ebf1 or Pax5 haploinsufficiency synergizes with STAT5 activation to initiate acute lymphoblastic leukemia. J. Exp. Med. 2011, 208, 1135–1149. [Google Scholar] [CrossRef] [PubMed]
- Burchill, M.A.; Goetz, C.A.; Prlic, M.; O’Neil, J.J.; Harmon, I.R.; Bensinger, S.J.; Turka, L.A.; Brennan, P.; Jameson, S.C.; Farrar, M.A. Distinct effects of STAT5 activation on CD4+ and CD8+ T cell homeostasis: Development of CD4+CD25+ regulatory T cells versus CD8+ memory T cells. J. Immunol. Baltim. Md 1950 2003, 171, 5853–5864. [Google Scholar] [CrossRef]
- Nutt, S.L.; Kee, B.L. The Transcriptional Regulation of B Cell Lineage Commitment. Immunity 2007, 26, 715–725. [Google Scholar] [CrossRef]
- Kanai, T.; Seki, S.; Jenks, J.A.; Kohli, A.; Kawli, T.; Martin, D.P.; Snyder, M.; Bacchetta, R.; Nadeau, K.C. Identification of STAT5A and STAT5B Target Genes in Human T Cells. PLoS ONE 2014, 9, e86790. [Google Scholar] [CrossRef] [PubMed]
- Hand, T.W.; Cui, W.; Jung, Y.W.; Sefik, E.; Joshi, N.S.; Chandele, A.; Liu, Y.; Kaech, S.M. Differential effects of STAT5 and PI3K/AKT signaling on effector and memory CD8 T-cell survival. Proc. Natl. Acad. Sci. USA 2010, 107, 16601–16606. [Google Scholar] [CrossRef] [PubMed]
- Tripathi, P.; Kurtulus, S.; Wojciechowski, S.; Sholl, A.; Hoebe, K.; Morris, S.C.; Finkelman, F.D.; Grimes, H.L.; Hildeman, D.A. STAT5 Is Critical To Maintain Effector CD8+ T Cell Responses. J. Immunol. 2010, 185, 2116–2124. [Google Scholar] [CrossRef]
- Park, J.-H.; Adoro, S.; Guinter, T.; Erman, B.; Alag, A.S.; Catalfamo, M.; Kimura, M.Y.; Cui, Y.; Lucas, P.J.; Gress, R.E.; et al. Signaling by intrathymic cytokines, not T cell antigen receptors, specifies CD8 lineage choice and promotes the differentiation of cytotoxic-lineage T cells. Nat. Immunol. 2010, 11, 257–264. [Google Scholar] [CrossRef]
- Halim, C.E.; Deng, S.; Ong, M.S.; Yap, C.T. Involvement of STAT5 in Oncogenesis. Biomedicines 2020, 8, 316. [Google Scholar] [CrossRef]
- Frank, D.A. StAT signaling in cancer: Insights into pathogenesis and treatment strategies. Cancer Treat. Res. 2003, 115, 267–291. [Google Scholar] [CrossRef]
- Nelson, E.A.; Walker, S.R.; Alvarez, J.V.; Frank, D.A. Isolation of Unique STAT5 Targets by Chromatin Immunoprecipitation-based Gene Identification. J. Biol. Chem. 2004, 279, 54724–54730. [Google Scholar] [CrossRef]
- Verhoeven, Y.; Tilborghs, S.; Jacobs, J.; De Waele, J.; Quatannens, D.; Deben, C.; Prenen, H.; Pauwels, P.; Trinh, X.B.; Wouters, A.; et al. The potential and controversy of targeting STAT family members in cancer. Semin. Cancer Biol. 2020, 60, 41–56. [Google Scholar] [CrossRef]
- Lin, W.; Schmidt, J.W.; Creamer, B.A.; Triplett, A.A.; Wagner, K.-U. Gain-of-Function of Stat5 Leads to Excessive Granulopoiesis and Lethal Extravasation of Granulocytes to the Lung. PLoS ONE 2013, 8, e60902. [Google Scholar] [CrossRef]
- Barash, I. Stat5 in breast cancer: Potential oncogenic activity coincides with positive prognosis for the disease. Carcinogenesis 2012, 33, 2320–2325. [Google Scholar] [CrossRef]
- Wagner, K.-U.; Rui, H. Jak2/Stat5 Signaling in Mammogenesis, Breast Cancer Initiation and Progression. J. Mammary Gland Biol. Neoplasia 2008, 13, 93–103. [Google Scholar] [CrossRef]
- Cotarla, I.; Ren, S.; Zhang, Y.; Gehan, E.; Singh, B.; Furth, P.A. Stat5a is tyrosine phosphorylated and nuclear localized in a high proportion of human breast cancers. Int. J. Cancer 2004, 108, 665–671. [Google Scholar] [CrossRef]
- Lin, M.; Ku, A.T.; Dong, J.; Yue, F.; Jiang, W.; Ibrahim, A.A.; Peng, F.; Creighton, C.J.; Nagi, C.; Gutierrez, C.; et al. STAT5 confers lactogenic properties in breast tumorigenesis and restricts metastatic potential. Oncogene 2022, 41, 5214–5222. [Google Scholar] [CrossRef] [PubMed]
- Walker, S.R.; Nelson, E.A.; Zou, L.; Chaudhury, M.; Signoretti, S.; Richardson, A.; Frank, D.A. Reciprocal Effects of STAT5 and STAT3 in Breast Cancer. Mol. Cancer Res. 2009, 7, 966–976. [Google Scholar] [CrossRef] [PubMed]
- Wingelhofer, B.; Neubauer, H.A.; Valent, P.; Han, X.; Constantinescu, S.N.; Gunning, P.T.; Müller, M.; Moriggl, R. Implications of STAT3 and STAT5 signaling on gene regulation and chromatin remodeling in hematopoietic cancer. Leukemia 2018, 32, 1713–1726. [Google Scholar] [CrossRef]
- Basso, K.; Dalla-Favera, R. Germinal centres and B cell lymphomagenesis. Nat. Rev. Immunol. 2015, 15, 172–184. [Google Scholar] [CrossRef]
- Walker, S.R.; Nelson, E.A.; Yeh, J.E.; Pinello, L.; Yuan, G.-C.; Frank, D.A. STAT5 Outcompetes STAT3 To Regulate the Expression of the Oncogenic Transcriptional Modulator BCL6. Mol. Cell. Biol. 2013, 33, 2879–2890. [Google Scholar] [CrossRef]
- van der Zwet, J.C.G.; Cordo’, V.; Buijs-Gladdines, J.G.C.A.M.; Hagelaar, R.; Smits, W.K.; Vroegindeweij, E.; Graus, L.T.M.; Poort, V.M.; Nulle, M.; Pieters, R.; et al. STAT5 does not drive steroid resistance in T-cell acute lymphoblastic leukemia despite the activation of BCL and BCLXL following glucocorticoid treatment. Haematologica 2022, 108, 732–746. [Google Scholar] [CrossRef]
- NCBI. STAT1 Signal Transducer and Activator of Transcription 1 [Homo Sapiens (Human)]-Gene. Available online: https://www.ncbi.nlm.nih.gov/gene/6772 (accessed on 6 January 2024).
- Dovhey, S.E.; Ghosh, N.S.; Wright, K.L. Loss of interferon-gamma inducibility of TAP1 and LMP2 in a renal cell carcinoma cell line. Cancer Res. 2000, 60, 5789–5796. [Google Scholar]
- Totten, S.P.; Im, Y.K.; Cepeda Cañedo, E.; Najyb, O.; Nguyen, A.; Hébert, S.; Ahn, R.; Lewis, K.; Lebeau, B.; La Selva, R.; et al. STAT1 potentiates oxidative stress revealing a targetable vulnerability that increases phenformin efficacy in breast cancer. Nat. Commun. 2021, 12, 3299. [Google Scholar] [CrossRef]
- Kovacic, B.; Stoiber, D.; Moriggl, R.; Weisz, E.; Ott, R.G.; Kreibich, R.; Levy, D.E.; Beug, H.; Freissmuth, M.; Sexl, V. STAT1 acts as a tumor promoter for leukemia development. Cancer Cell 2006, 10, 77–87. [Google Scholar] [CrossRef]
- Park, C.; Li, S.; Cha, E.; Schindler, C. Immune Response in Stat2 Knockout Mice. Immunity 2000, 13, 795–804. [Google Scholar] [CrossRef]
- Hambleton, S.; Goodbourn, S.; Young, D.F.; Dickinson, P.; Mohamad, S.M.B.; Valappil, M.; McGovern, N.; Cant, A.J.; Hackett, S.J.; Ghazal, P.; et al. STAT2 deficiency and susceptibility to viral illness in humans. Proc. Natl. Acad. Sci. USA 2013, 110, 3053–3058. [Google Scholar] [CrossRef] [PubMed]
- Canar, J.; Darling, K.; Dadey, R.; Gamero, A.M. The duality of STAT2 mediated type I interferon signaling in the tumor microenvironment and chemoresistance. Cytokine 2023, 161, 156081. [Google Scholar] [CrossRef] [PubMed]
- Lee, C.-J.; An, H.-J.; Kim, S.-M.; Yoo, S.-M.; Park, J.; Lee, G.-E.; Kim, W.-Y.; Kim, D.J.; Kang, H.C.; Lee, J.Y.; et al. FBXW7-mediated stability regulation of signal transducer and activator of transcription 2 in melanoma formation. Proc. Natl. Acad. Sci. USA 2020, 117, 584–594. [Google Scholar] [CrossRef] [PubMed]
- Zhou, L.; Li, Y.; Li, Z.; Huang, Q. Mining therapeutic and prognostic significance of STATs in renal cell carcinoma with bioinformatics analysis. Genomics 2020, 112, 4100–4114. [Google Scholar] [CrossRef] [PubMed]
- Zhou, X.-Y.; Dai, H.-Y.; Zhang, H.; Zhu, J.-L.; Hu, H. Signal transducer and activator of transcription family is a prognostic marker associated with immune infiltration in endometrial cancer. J. Clin. Lab. Anal. 2022, 36, e24315. [Google Scholar] [CrossRef] [PubMed]
- Huang, Y.-C.; Huang, J.-L.; Tseng, L.-C.; Yu, P.-H.; Chen, S.-Y.; Lin, C.-S. High Expression of Interferon Pathway Genes CXCL10 and STAT2 Is Associated with Activated T-Cell Signature and Better Outcome of Oral Cancer Patients. J. Pers. Med. 2022, 12, 140. [Google Scholar] [CrossRef] [PubMed]
- Nguyen, K.B.; Watford, W.T.; Salomon, R.; Hofmann, S.R.; Pien, G.C.; Morinobu, A.; Gadina, M.; O’Shea, J.J.; Biron, C.A. Critical role for STAT4 activation by type 1 interferons in the interferon-gamma response to viral infection. Science 2002, 297, 2063–2066. [Google Scholar] [CrossRef] [PubMed]
- Parham, C.; Chirica, M.; Timans, J.; Vaisberg, E.; Travis, M.; Cheung, J.; Pflanz, S.; Zhang, R.; Singh, K.P.; Vega, F.; et al. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R. J. Immunol. Baltim. Md 1950 2002, 168, 5699–5708. [Google Scholar] [CrossRef]
- Bacon, C.M.; Petricoin, E.F.; Ortaldo, J.R.; Rees, R.C.; Larner, A.C.; Johnston, J.A.; O’Shea, J.J. Interleukin 12 induces tyrosine phosphorylation and activation of STAT4 in human lymphocytes. Proc. Natl. Acad. Sci. USA 1995, 92, 7307–7311. [Google Scholar] [CrossRef] [PubMed]
- Zhao, L.; Ji, G.; Le, X.; Luo, Z.; Wang, C.; Feng, M.; Xu, L.; Zhang, Y.; Lau, W.B.; Lau, B.; et al. An integrated analysis identifies STAT4 as a key regulator of ovarian cancer metastasis. Oncogene 2017, 36, 3384–3396. [Google Scholar] [CrossRef] [PubMed]
- Anderson, K.; Ryan, N.; Volpedo, G.; Varikuti, S.; Satoskar, A.R.; Oghumu, S. Immune Suppression Mediated by STAT4 Deficiency Promotes Lymphatic Metastasis in HNSCC. Front. Immunol. 2020, 10, 3095. [Google Scholar] [CrossRef]
- Nishi, M.; Batsaikhan, B.-E.; Yoshikawa, K.; Higashijima, J.; Tokunaga, T.; Takasu, C.; Kashihara, H.; Ishikawa, D.; Shimada, M. High STAT4 Expression Indicates Better Disease-free Survival in Patients with Gastric Cancer. Anticancer Res. 2017, 37, 6723–6729. [Google Scholar]
- Goenka, S.; Kaplan, M.H. Transcriptional regulation by STAT6. Immunol. Res. 2011, 50, 87–96. [Google Scholar] [CrossRef] [PubMed]
- Delgado-Ramirez, Y.; Colly, V.; Gonzalez, G.V.; Leon-Cabrera, S. Signal transducer and activator of transcription 6 as a target in colon cancer therapy. Oncol. Lett. 2020, 20, 455–464. [Google Scholar] [CrossRef] [PubMed]
- Di Stefano, A.B.; Iovino, F.; Lombardo, Y.; Eterno, V.; Höger, T.; Dieli, F.; Stassi, G.; Todaro, M. Survivin is regulated by interleukin-4 in colon cancer stem cells. J. Cell. Physiol. 2010, 225, 555–561. [Google Scholar] [CrossRef] [PubMed]
- Jayakumar, A.; Bothwell, A.L.M. Stat6 Promotes Intestinal Tumorigenesis in a Mouse Model of Adenomatous Polyposis by Expansion of MDSCs and Inhibition of Cytotoxic CD8 Response. Neoplasia 2017, 19, 595–605. [Google Scholar] [CrossRef] [PubMed]
- Binnemars-Postma, K.; Bansal, R.; Storm, G.; Prakash, J. Targeting the Stat6 pathway in tumor-associated macrophages reduces tumor growth and metastatic niche formation in breast cancer. FASEB J. 2018, 32, 969–978. [Google Scholar] [CrossRef] [PubMed]
- Iqbal, J.; Abbasi, B.A.; Ahmad, R.; Mahmood, T.; Ali, B.; Khalil, A.T.; Kanwal, S.; Shah, S.A.; Alam, M.M.; Badshah, H.; et al. Nanomedicines for developing cancer nanotherapeutics: From benchtop to bedside and beyond. Appl. Microbiol. Biotechnol. 2018, 102, 9449–9470. [Google Scholar] [CrossRef] [PubMed]
- Hong, D.; Kurzrock, R.; Kim, Y.; Woessner, R.; Younes, A.; Nemunaitis, J.; Fowler, N.; Zhou, T.; Schmidt, J.; Jo, M.; et al. AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma and lung cancer. Sci. Transl. Med. 2015, 7, 314ra185. [Google Scholar] [CrossRef] [PubMed]
- Reilley, M.J.; McCoon, P.; Cook, C.; Lyne, P.; Kurzrock, R.; Kim, Y.; Woessner, R.; Younes, A.; Nemunaitis, J.; Fowler, N.; et al. STAT3 antisense oligonucleotide AZD9150 in a subset of patients with heavily pretreated lymphoma: Results of a phase 1b trial. J. Immunother. Cancer 2018, 6, 119. [Google Scholar] [CrossRef]
- Bai, L.; Zhou, H.; Xu, R.; Zhao, Y.; Chinnaswamy, K.; McEachern, D.; Chen, J.; Yang, C.-Y.; Liu, Z.; Wang, M.; et al. A Potent and Selective Small-Molecule Degrader of STAT3 Achieves Complete Tumor Regression In Vivo. Cancer Cell 2019, 36, 498–511.e17. [Google Scholar] [CrossRef]
- Holland, S.M.; DeLeo, F.R.; Elloumi, H.Z.; Hsu, A.P.; Uzel, G.; Brodsky, N.; Freeman, A.F.; Demidowich, A.; Davis, J.; Turner, M.L.; et al. STAT3 mutations in the hyper-IgE syndrome. N. Engl. J. Med. 2007, 357, 1608–1619. [Google Scholar] [CrossRef]
- Minegishi, Y.; Saito, M.; Tsuchiya, S.; Tsuge, I.; Takada, H.; Hara, T.; Kawamura, N.; Ariga, T.; Pasic, S.; Stojkovic, O.; et al. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature 2007, 448, 1058–1062. [Google Scholar] [CrossRef] [PubMed]
- Levy, D.E.; Loomis, C.A. STAT3 Signaling and the Hyper-IgE Syndrome. N. Engl. J. Med. 2007, 357, 1655–1658. [Google Scholar] [CrossRef] [PubMed]
- Rhodes, R.T. Understanding Hyper IgE Syndrome. IG Living 2020, 2020, 34–39. [Google Scholar]
- Furqan, M.; Akinleye, A.; Mukhi, N.; Mittal, V.; Chen, Y.; Liu, D. STAT inhibitors for cancer therapy. J. Hematol. Oncol. 2013, 6, 90. [Google Scholar] [CrossRef] [PubMed]
- Bharadwaj, U.; Kasembeli, M.M.; Tweardy, D.J. STAT3 Inhibitors in Cancer: A Comprehensive Update. In STAT Inhibitors in Cancer; Ward, A.C., Ed.; Springer International Publishing: Cham, Switzerland, 2016; pp. 95–161. ISBN 978-3-319-42947-2. [Google Scholar]
- Bhullar, K.S.; Lagarón, N.O.; McGowan, E.M.; Parmar, I.; Jha, A.; Hubbard, B.P.; Rupasinghe, H.P.V. Kinase-targeted cancer therapies: Progress, challenges and future directions. Mol. Cancer 2018, 17, 48. [Google Scholar] [CrossRef]
- Cohen, P.; Cross, D.; Jänne, P.A. Kinase drug discovery 20 years after imatinib: Progress and future directions. Nat. Rev. Drug Discov. 2021, 20, 551–569. [Google Scholar] [CrossRef]
- Lovly, C.M.; Shaw, A.T. Molecular Pathways: Resistance to Kinase Inhibitors and Implications for Therapeutic Strategies. Clin. Cancer Res. 2014, 20, 2249–2256. [Google Scholar] [CrossRef] [PubMed]
- Rosenzweig, S.A. Acquired Resistance to Drugs Targeting Tyrosine Kinases. Adv. Cancer Res. 2018, 138, 71–98. [Google Scholar] [CrossRef]
- Benedettini, E.; Sholl, L.M.; Peyton, M.; Reilly, J.; Ware, C.; Davis, L.; Vena, N.; Bailey, D.; Yeap, B.Y.; Fiorentino, M.; et al. Met activation in non-small cell lung cancer is associated with de novo resistance to EGFR inhibitors and the development of brain metastasis. Am. J. Pathol. 2010, 177, 415–423. [Google Scholar] [CrossRef]
- Zou, S.; Tong, Q.; Liu, B.; Huang, W.; Tian, Y.; Fu, X. Targeting STAT3 in Cancer Immunotherapy. Mol. Cancer 2020, 19, 145. [Google Scholar] [CrossRef]
- Demela, P.; Pirastu, N.; Soskic, B. Cross-disorder genetic analysis of immune diseases reveals distinct gene associations that converge on common pathways. Nat. Commun. 2023, 14, 2743. [Google Scholar] [CrossRef] [PubMed]
- Sarapultsev, A.; Gusev, E.; Komelkova, M.; Utepova, I.; Luo, S.; Hu, D. JAK-STAT signaling in inflammation and stress-related diseases: Implications for therapeutic interventions. Mol. Biomed. 2023, 4, 40. [Google Scholar] [CrossRef] [PubMed]
- Koehler, A.N. A complex task? Direct modulation of transcription factors with small molecules. Curr. Opin. Chem. Biol. 2010, 14, 331–340. [Google Scholar] [CrossRef] [PubMed]
- Xie, X.; Yu, T.; Li, X.; Zhang, N.; Foster, L.J.; Peng, C.; Huang, W.; He, G. Recent advances in targeting the “undruggable” proteins: From drug discovery to clinical trials. Signal Transduct. Target. Ther. 2023, 8, 1–71. [Google Scholar] [CrossRef] [PubMed]
- Xu, X.; Kasembeli, M.M.; Jiang, X.; Tweardy, B.J.; Tweardy, D.J. Chemical probes that competitively and selectively inhibit Stat3 activation. PLoS ONE 2009, 4, e4783. [Google Scholar] [CrossRef]
- Chen, H.; Bian, A.; Yang, L.; Yin, X.; Wang, J.; Ti, C.; Miao, Y.; Peng, S.; Xu, S.; Liu, M.; et al. Targeting STAT3 by a small molecule suppresses pancreatic cancer progression. Oncogene 2021, 40, 1440. [Google Scholar] [CrossRef] [PubMed]
- Nelson, E.A.; Sharma, S.V.; Settleman, J.; Frank, D.A. A chemical biology approach to developing STAT inhibitors: Molecular strategies for accelerating clinical translation. Oncotarget 2011, 2, 518–524. [Google Scholar] [CrossRef]
- Jackson, P.J.M.; Jamshidi, S.; Farag, D.B. Computational Approaches in the Development of Small-molecule Transcription Factor Inhibitors; Royal Society of Chemistry: London, UK, 2018. [Google Scholar] [CrossRef]
- Yue, P.; Turkson, J. Targeting STAT3 in cancer: How successful are we? Expert Opin. Investig. Drugs 2009, 18, 45–56. [Google Scholar] [CrossRef]
- Hemmann, U.; Gerhartz, C.; Heesel, B.; Sasse, J.; Kurapkat, G.; Grötzinger, J.; Wollmer, A.; Zhong, Z.; Darnell, J.E.; Graeve, L.; et al. Differential Activation of Acute Phase Response Factor/Stat3 and Stat1 via the Cytoplasmic Domain of the Interleukin 6 Signal Transducer gp130. J. Biol. Chem. 1996, 271, 12999–13007. [Google Scholar] [CrossRef]
- Diop, A.; Santorelli, D.; Malagrinò, F.; Nardella, C.; Pennacchietti, V.; Pagano, L.; Marcocci, L.; Pietrangeli, P.; Gianni, S.; Toto, A. SH2 Domains: Folding, Binding and Therapeutical Approaches. Int. J. Mol. Sci. 2022, 23, 15944. [Google Scholar] [CrossRef]
- Bharadwaj, U.; Eckols, T.K.; Xu, X.; Kasembeli, M.M.; Chen, Y.; Adachi, M.; Song, Y.; Mo, Q.; Lai, S.Y.; Tweardy, D.J. Small-molecule inhibition of STAT3 in radioresistant head and neck squamous cell carcinoma. Oncotarget 2016, 7, 26307–26330. [Google Scholar] [CrossRef] [PubMed]
- Cerulli, R.A.; Kritzer, J.A. Phosphotyrosine Isosteres: Past, Present and Future. Org. Biomol. Chem. 2020, 18, 583–605. [Google Scholar] [CrossRef] [PubMed]
- Shi, Z.; Zhou, Q.; Gao, S.; Li, W.; Li, X.; Liu, Z.; Jin, P.; Jiang, J. Silibinin inhibits endometrial carcinoma via blocking pathways of STAT3 activation and SREBP1-mediated lipid accumulation. Life Sci. 2019, 217, 70–80. [Google Scholar] [CrossRef] [PubMed]
- Ye, C.; Ruan, X.; Zhao, Y.; Zhu, H.; Wang, C.; Cheng, Z.; Peng, H. BP-1-102 exerts antitumor effects on T-cell acute lymphoblastic leukemia cells by suppressing the JAK2/STAT3/c-Myc signaling pathway. Exp. Ther. Med. 2023, 25, 191. [Google Scholar] [CrossRef] [PubMed]
- Zhang, R.; Chen, X.; Fu, S.; Xu, L.; Lin, J. A small molecule STAT3 inhibitor, LLL12, enhances cisplatin- and paclitaxel-mediated inhibition of cell growth and migration in human ovarian cancer cells. Oncol. Rep. 2020, 44, 1224–1232. [Google Scholar] [CrossRef] [PubMed]
- Brown, J.R.; Walker, S.R.; Heppler, L.N.; Tyekucheva, S.; Nelson, E.A.; Klitgaard, J.; Nicolais, M.; Kroll, Y.; Xiang, M.; Yeh, J.E.; et al. Targeting constitutively active STAT3 in chronic lymphocytic leukemia: A clinical trial of the STAT3 inhibitor pyrimethamine with pharmacodynamic analyses. Am. J. Hematol. 2021, 96, E95–E98. [Google Scholar] [CrossRef] [PubMed]
- Brambilla, L.; Lahiri, T.; Cammer, M.; Levy, D.E. STAT3 Inhibitor OPB-51602 Is Cytotoxic to Tumor Cells Through Inhibition of Complex I and ROS Induction. iScience 2020, 23, 101822. [Google Scholar] [CrossRef] [PubMed]
- Skwarski, M.; McGowan, D.R.; Belcher, E.; Di Chiara, F.; Stavroulias, D.; McCole, M.; Derham, J.L.; Chu, K.-Y.; Teoh, E.; Chauhan, J.; et al. Mitochondrial Inhibitor Atovaquone Increases Tumor Oxygenation and Inhibits Hypoxic Gene Expression in Patients with Non-Small Cell Lung Cancer. Clin. Cancer Res. 2021, 27, 2459–2469. [Google Scholar] [CrossRef] [PubMed]
- Stevens, A.M.; Xiang, M.; Heppler, L.N.; Tošić, I.; Jiang, K.; Munoz, J.O.; Gaikwad, A.S.; Horton, T.M.; Long, X.; Narayanan, P.; et al. Atovaquone is active against AML by upregulating the integrated stress pathway and suppressing oxidative phosphorylation. Blood Adv. 2019, 3, 4215–4227. [Google Scholar] [CrossRef]
- Qi, X.; Li, M.; Zhang, X.-M.; Dai, X.-F.; Cui, J.; Li, D.-H.; Gu, Q.-Q.; Lv, Z.-H.; Li, J. Trichothecin Inhibits Cancer-Related Features in Colorectal Cancer Development by Targeting STAT3. Molecules 2020, 25, 2306. [Google Scholar] [CrossRef]
- Li, H.; Wang, L.; Cao, F.; Yu, D.; Yang, J.; Yu, X.; Dong, J.; Qin, J.J.; Guan, X. Design, synthesis, and biological characterization of a potent STAT3 degrader for the treatment of gastric cancer. Front. Pharmacol. 2022, 13, 944455. [Google Scholar] [CrossRef]
- Kaneshige, A.; Bai, L.; Wang, M.; McEachern, D.; Meagher, J.L.; Xu, R.; Wang, Y.; Jiang, W.; Metwally, H.; Kirchhoff, P.D.; et al. A selective small-molecule STAT5 PROTAC degrader capable of achieving tumor regression in vivo. Nat. Chem. Biol. 2023, 19, 703–711. [Google Scholar] [CrossRef]
- Roschewski, M.; Patel, M.R.; Reagan, P.M.; Saba, N.S.; Collins, G.P.; Arkenau, H.-T.; de Vos, S.; Nuttall, B.; Acar, M.; Burke, K.; et al. Phase I Study of Acalabrutinib Plus Danvatirsen (AZD9150) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma Including Circulating Tumor DNA Biomarker Assessment. Clin. Cancer Res. 2023, 29, 3301–3312. [Google Scholar] [CrossRef]
- Nishina, T.; Fujita, T.; Yoshizuka, N.; Sugibayashi, K.; Murayama, K.; Kuboki, Y. Safety, tolerability, pharmacokinetics and preliminary antitumour activity of an antisense oligonucleotide targeting STAT3 (danvatirsen) as monotherapy and in combination with durvalumab in Japanese patients with advanced solid malignancies: A phase 1 study. BMJ Open 2022, 12, e055718. [Google Scholar] [CrossRef]
- Casas, G.; Perche, F.; Midoux, P.; Pichon, C.; Malinge, J.-M. DNA minicircles as novel STAT3 decoy oligodeoxynucleotides endowed with anticancer activity in triple-negative breast cancer. Mol. Ther. Nucleic Acids 2022, 29, 162–175. [Google Scholar] [CrossRef] [PubMed]
- Aftabizadeh, M.; Li, Y.-J.; Zhao, Q.; Zhang, C.; Ambaye, N.; Song, J.; Nagao, T.; Lahtz, C.; Fakih, M.; Ann, D.K.; et al. Potent antitumor effects of cell-penetrating peptides targeting STAT3 axis. JCI Insight 2021, 6, e136176. [Google Scholar] [CrossRef] [PubMed]
- Oleksak, P.; Psotka, M.; Vancurova, M.; Sapega, O.; Bieblova, J.; Reinis, M.; Rysanek, D.; Mikyskova, R.; Chalupova, K.; Malinak, D.; et al. Design, synthesis, and in vitro evaluation of BP-1-102 analogs with modified hydrophobic fragments for STAT3 inhibition. J. Enzyme Inhib. Med. Chem. 2021, 36, 410–424. [Google Scholar] [CrossRef]
- Gu, Y.; Mohammad, I.S.; Liu, Z. Overview of the STAT-3 signaling pathway in cancer and the development of specific inhibitors (Review). Oncol. Lett. 2020, 19, 2585–2594. [Google Scholar] [CrossRef] [PubMed]
- Wang, D.; Xu, M.; Li, F.; Gao, Y.; Sun, H. Target Identification-Based Analysis of Mechanism of Betulinic Acid-Induced Cells Apoptosis of Cervical Cancer SiHa. Nat. Prod. Commun. 2022, 17, 1934578X221115528. [Google Scholar] [CrossRef]
- Zhao, L.; Zhao, J.; Zhong, K.; Tong, A.; Jia, D. Targeted protein degradation: Mechanisms, strategies and application. Signal Transduct. Target. Ther. 2022, 7, 113. [Google Scholar] [CrossRef]
- Sakamoto, K.M.; Kim, K.B.; Kumagai, A.; Mercurio, F.; Crews, C.M.; Deshaies, R.J. Protacs: Chimeric molecules that target proteins to the Skp1–Cullin–F box complex for ubiquitination and degradation. Proc. Natl. Acad. Sci. USA 2001, 98, 8554–8559. [Google Scholar] [CrossRef] [PubMed]
- Potjewyd, F.; Turner, A.-M.W.; Beri, J.; Rectenwald, J.M.; Norris-Drouin, J.L.; Cholensky, S.H.; Margolis, D.M.; Pearce, K.H.; Herring, L.E.; James, L.I. Degradation of Polycomb Repressive Complex 2 with an EED-Targeted Bivalent Chemical Degrader. Cell Chem. Biol. 2020, 27, 47–56.e15. [Google Scholar] [CrossRef] [PubMed]
- Qi, S.-M.; Dong, J.; Xu, Z.-Y.; Cheng, X.-D.; Zhang, W.-D.; Qin, J.-J. PROTAC: An Effective Targeted Protein Degradation Strategy for Cancer Therapy. Front. Pharmacol. 2021, 12, 692574. [Google Scholar] [CrossRef] [PubMed]
- He, M.; Lv, W.; Rao, Y. Opportunities and Challenges of Small Molecule Induced Targeted Protein Degradation. Front. Cell Dev. Biol. 2021, 9, 685106. [Google Scholar] [CrossRef]
- Zhou, H.; Bai, L.; Xu, R.; Zhao, Y.; Chen, J.; McEachern, D.; Chinnaswamy, K.; Wen, B.; Dai, L.; Kumar, P.; et al. Structure-Based Discovery of SD-36 as a Potent, Selective, and Efficacious PROTAC Degrader of STAT3 Protein. J. Med. Chem. 2019, 62, 11280–11300. [Google Scholar] [CrossRef] [PubMed]
- Kong, S.; Ge, X.; Li, X.; Liu, Z.; Zhang, R.; Yang, M.; Wang, Z.; Li, Z. SD-36 promotes growth inhibition and induces apoptosis via suppression of Mcl-1 in glioma. J. Cell. Mol. Med. 2021, 25, 8261–8270. [Google Scholar] [CrossRef]
- Zhou, H.; Bai, L.; Xu, R.; McEachern, D.; Chinnaswamy, K.; Li, R.; Wen, B.; Wang, M.; Yang, C.-Y.; Meagher, J.L.; et al. SD-91 as A Potent and Selective STAT3 Degrader Capable of Achieving Complete and Long-Lasting Tumor Regression. ACS Med. Chem. Lett. 2021, 12, 996–1004. [Google Scholar] [CrossRef] [PubMed]
- Shastri, A. Preliminary Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of KT-333, a Targeted Protein Degrader of STAT3, in Patients with Relapsed or Refractory Lymphomas, Large Granular Lymphocytic Leukemia, and Solid Tumors; ASH: Washington, DC, USA, 2023. [Google Scholar]
- Sasso, J.M.; Tenchov, R.; Wang, D.; Johnson, L.S.; Wang, X.; Zhou, Q.A. Molecular Glues: The Adhesive Connecting Targeted Protein Degradation to the Clinic. Biochemistry 2022, 62, 601–623. [Google Scholar] [CrossRef] [PubMed]
- Dong, G.; Ding, Y.; He, S.; Sheng, C. Molecular Glues for Targeted Protein Degradation: From Serendipity to Rational Discovery. J. Med. Chem. 2021, 64, 10606–10620. [Google Scholar] [CrossRef]
- den Besten, W.; Lipford, J.R. Prospecting for molecular glues. Nat. Chem. Biol. 2020, 16, 1157–1158. [Google Scholar] [CrossRef]
- Johnson, D.E.; O’Keefe, R.A.; Grandis, J.R. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat. Rev. Clin. Oncol. 2018, 15, 234–248. [Google Scholar] [CrossRef] [PubMed]
- Ohsugi, Y.; Tsuchimoto, N. [Pharmacological and clinical profile of anti-human IL-6 receptor antibody (tocilizumab, ACTEMRA), a novel therapeutic drug for Castleman’s disease]. Nihon Yakurigaku Zasshi 2005, 126, 419–425. [Google Scholar] [CrossRef]
- Sheppard, M.; Laskou, F.; Stapleton, P.P.; Hadavi, S.; Dasgupta, B. Tocilizumab (Actemra). Hum. Vaccines Immunother. 2017, 13, 1972–1988. [Google Scholar] [CrossRef] [PubMed]
- Salgado, R.; Junius, S.; Benoy, I.; Van Dam, P.; Vermeulen, P.; Van Marck, E.; Huget, P.; Dirix, L.Y. Circulating interleukin-6 predicts survival in patients with metastatic breast cancer. Int. J. Cancer 2003, 103, 642–646. [Google Scholar] [CrossRef] [PubMed]
- Lippitz, B.E.; Harris, R.A. Cytokine patterns in cancer patients: A review of the correlation between interleukin 6 and prognosis. Oncoimmunology 2016, 5, e1093722. [Google Scholar] [CrossRef] [PubMed]
- Hu, X.; Li, J.; Fu, M.; Zhao, X.; Wang, W. The JAK/STAT signaling pathway: From bench to clinic. Signal Transduct. Target. Ther. 2021, 6, 402. [Google Scholar] [CrossRef]
- Morris, R.; Kershaw, N.J.; Babon, J.J. The molecular details of cytokine signaling via the JAK/STAT pathway. Protein Sci. 2018, 27, 1984–2009. [Google Scholar] [CrossRef] [PubMed]
- Schwartz, D.M.; Kanno, Y.; Villarino, A.; Ward, M.; Gadina, M.; O’Shea, J.J. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat. Rev. Drug Discov. 2017, 17, 78. [Google Scholar] [CrossRef] [PubMed]
- Winthrop, K.L.; Cohen, S.B. Oral surveillance and JAK inhibitor safety: The theory of relativity. Nat. Rev. Rheumatol. 2022, 18, 301–304. [Google Scholar] [CrossRef]
- von Locquenghien, M.; Rozalén, C.; Celià-Terrassa, T. Interferons in cancer immunoediting: Sculpting metastasis and immunotherapy response. J. Clin. Investig. 2021, 131, e143296. [Google Scholar] [CrossRef]
- Ribas, A.; Haining, W.N.; Schumacher, T.N.M. When Cancer Cells Become the Enablers of an Antitumor Immune Response. Cancer Discov. 2022, 12, 2244–2248. [Google Scholar] [CrossRef]
- Melo, J.V. The molecular biology of chronic myeloid leukaemia. Leukemia 1996, 10, 751–756. [Google Scholar]
- Frank, D.A.; Varticovski, L. BCR/abl leads to the constitutive activation of Stat proteins, and shares an epitope with tyrosine phosphorylated Stats. Leukemia 1996, 10, 1724–1730. [Google Scholar] [PubMed]
- Carlesso, N.; Frank, D.A.; Griffin, J.D. Tyrosyl phosphorylation and DNA binding activity of signal transducers and activators of transcription (STAT) proteins in hematopoietic cell lines transformed by Bcr/Abl. J. Exp. Med. 1996, 183, 811–820. [Google Scholar] [CrossRef]
- Yanagisawa, K.; Yamauchi, H.; Kaneko, M.; Kohno, H.; Hasegawa, H.; Fujita, S. Suppression of cell proliferation and the expression of a bcr-abl fusion gene and apoptotic cell death in a new human chronic myelogenous leukemia cell line, KT-1, by interferon-alpha. Blood 1998, 91, 641–648. [Google Scholar] [CrossRef] [PubMed]
- Hoelbl, A.; Schuster, C.; Kovacic, B.; Zhu, B.; Wickre, M.; Hoelzl, M.A.; Fajmann, S.; Grebien, F.; Warsch, W.; Stengl, G.; et al. Stat5 is indispensable for the maintenance of bcr/abl-positive leukaemia. EMBO Mol. Med. 2010, 2, 98–110. [Google Scholar] [CrossRef] [PubMed]
- Hantschel, O.; Warsch, W.; Eckelhart, E.; Kaupe, I.; Grebien, F.; Wagner, K.-U.; Superti-Furga, G.; Sexl, V. BCR-ABL uncouples canonical JAK2-STAT5 signaling in chronic myeloid leukemia. Nat. Chem. Biol. 2012, 8, 285–293. [Google Scholar] [CrossRef] [PubMed]
- Rossari, F.; Minutolo, F.; Orciuolo, E. Past, present, and future of Bcr-Abl inhibitors: From chemical development to clinical efficacy. J. Hematol. Oncol. 2018, 11, 84. [Google Scholar] [CrossRef] [PubMed]
- Nelson, E.A.; Walker, S.R.; Weisberg, E.; Bar-Natan, M.; Barrett, R.; Gashin, L.B.; Terrell, S.; Klitgaard, J.L.; Santo, L.; Addorio, M.R.; et al. The STAT5 inhibitor pimozide decreases survival of chronic myelogenous leukemia cells resistant to kinase inhibitors. Blood 2011, 117, 3421–3429. [Google Scholar] [CrossRef]
- Bar-Natan, M.; Nelson, E.A.; Walker, S.R.; Kuang, Y.; Distel, R.J.; Frank, D.A. Dual inhibition of Jak2 and STAT5 enhances killing of myeloproliferative neoplasia cells. Leukemia 2012, 26, 1407–1410. [Google Scholar] [CrossRef]
- Kentsis, A.; Reed, C.; Rice, K.L.; Sanda, T.; Rodig, S.J.; Tholouli, E.; Christie, A.; Valk, P.J.M.; Delwel, R.; Ngo, V.; et al. Autocrine activation of the MET receptor tyrosine kinase in acute myeloid leukemia. Nat. Med. 2012, 18, 1118–1122. [Google Scholar] [CrossRef]
- Naldini, L.; Weidner, K.M.; Vigna, E.; Gaudino, G.; Bardelli, A.; Ponzetto, C.; Narsimhan, R.P.; Hartmann, G.; Zarnegar, R.; Michalopoulos, G.K. Scatter factor and hepatocyte growth factor are indistinguishable ligands for the MET receptor. EMBO J. 1991, 10, 2867–2878. [Google Scholar] [CrossRef]
- McGee, S.; Kornblau, S.; Qiu, Y.; Look, A.; Zhang, N.; Yoo, S.-Y.; Coombes, K.; Kentsis, A. Biological properties of ligand-dependent activation of the MET receptor kinase in acute myeloid leukemia. Leukemia 2015, 29, 1218–1221. [Google Scholar] [CrossRef]
- Kim, B.; Wang, S.; Lee, J.M.; Jeong, Y.; Ahn, T.; Son, D.-S.; Park, H.W.; Yoo, H.-s.; Song, Y.-J.; Lee, E.; et al. Synthetic lethal screening reveals FGFR as one of the combinatorial targets to overcome resistance to Met-targeted therapy. Oncogene 2015, 34, 1083–1093. [Google Scholar] [CrossRef]
- Chen, E.C.; Gandler, H.; Tošić, I.; Fell, G.G.; Fiore, A.; Pozdnyakova, O.; DeAngelo, D.J.; Galinsky, I.; Luskin, M.R.; Wadleigh, M.; et al. Targeting MET and FGFR in Relapsed or Refractory Acute Myeloid Leukemia: Preclinical and Clinical Findings, and Signal Transduction Correlates. Clin. Cancer Res. 2023, 29, 878–887. [Google Scholar] [CrossRef]
- Zhao, C.; Li, H.; Lin, H.-J.; Yang, S.; Lin, J.; Liang, G. Feedback Activation of STAT3 as a Cancer Drug-Resistance Mechanism. Trends Pharmacol. Sci. 2016, 37, 47–61. [Google Scholar] [CrossRef]
- Heppler, L.N.; Frank, D.A. Targeting Oncogenic Transcription Factors: Therapeutic Implications of Endogenous STAT Inhibitors. Trends Cancer 2017, 3, 816–827. [Google Scholar] [CrossRef]
- Verlinde, C.L.; Hol, W.G. Structure-based drug design: Progress, results and challenges. Structure 1994, 2, 577–587. [Google Scholar] [CrossRef]
- Chen, A.; Koehler, A.N. Transcription Factor Inhibition: Lessons Learned and Emerging Targets. Trends Mol. Med. 2020, 26, 508–518. [Google Scholar] [CrossRef] [PubMed]
- Nelson, E.A.; Walker, S.R.; Kepich, A.; Gashin, L.B.; Hideshima, T.; Ikeda, H.; Chauhan, D.; Anderson, K.C.; Frank, D.A. Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT3. Blood 2008, 112, 5095–5102. [Google Scholar] [CrossRef] [PubMed]
- Xiang, M.; Kim, H.; Ho, V.T.; Walker, S.R.; Bar-Natan, M.; Anahtar, M.; Liu, S.; Toniolo, P.A.; Kroll, Y.; Jones, N.; et al. Gene expression-based discovery of atovaquone as a STAT3 inhibitor and anticancer agent. Blood 2016, 128, 1845–1853. [Google Scholar] [CrossRef] [PubMed]
- Hirschenberger, M.; Hayn, M.; Laliberté, A.; Koepke, L.; Kirchhoff, F.; Sparrer, K.M.J. Luciferase reporter assays to monitor interferon signaling modulation by SARS-CoV-2 proteins. STAR Protoc. 2021, 2, 100781. [Google Scholar] [CrossRef] [PubMed]
- Walker, S.R.; Frank, D.A. Screening approaches to generating STAT inhibitors. JAK-STAT 2012, 1, 292–299. [Google Scholar] [CrossRef] [PubMed]
- Nelson, E.A.; Walker, S.R.; Xiang, M.; Weisberg, E.; Bar-Natan, M.; Barrett, R.; Liu, S.; Kharbanda, S.; Christie, A.L.; Nicolais, M.; et al. The STAT5 Inhibitor Pimozide Displays Efficacy in Models of Acute Myelogenous Leukemia Driven by FLT3 Mutations. Genes Cancer 2012, 3, 503–511. [Google Scholar] [CrossRef] [PubMed]
- Takakura, A.; Nelson, E.A.; Haque, N.; Humphreys, B.D.; Zandi-Nejad, K.; Frank, D.A.; Zhou, J. Pyrimethamine inhibits adult polycystic kidney disease by modulating STAT signaling pathways. Hum. Mol. Genet. 2011, 20, 4143–4154. [Google Scholar] [CrossRef]
- Khan, M.W.; Saadalla, A.; Ewida, A.H.; Al-Katranji, K.; Al-Saoudi, G.; Giaccone, Z.T.; Gounari, F.; Zhang, M.; Frank, D.A.; Khazaie, K. The STAT3 inhibitor pyrimethamine displays anti-cancer and immune stimulatory effects in murine models of breast cancer. Cancer Immunol. Immunother. 2018, 67, 13–23. [Google Scholar] [CrossRef]
- Heppler, L.N.; Attarha, S.; Persaud, R.; Brown, J.I.; Wang, P.; Petrova, B.; Tošić, I.; Burton, F.B.; Flamand, Y.; Walker, S.R.; et al. The antimicrobial drug pyrimethamine inhibits STAT3 transcriptional activity by targeting the enzyme dihydrofolate reductase. J. Biol. Chem. 2022, 298, 101531. [Google Scholar] [CrossRef] [PubMed]
- Brown, J.I.; Persaud, R.; Iliev, P.; Karmacharya, U.; Attarha, S.; Sahile, H.; Olsen, J.E.; Hanke, D.; Idowu, T.; Frank, D.A.; et al. Investigating the anti-cancer potential of pyrimethamine analogues through a modern chemical biology lens. Eur. J. Med. Chem. 2024, 264, 115971. [Google Scholar] [CrossRef]
- Centers for Disease Control and Prevention. Toxoplasmosis-Resources for Health Professionals. Available online: https://www.cdc.gov/parasites/toxoplasmosis/health_professionals/index.html (accessed on 8 January 2024).
- Frank, D.A.; Mahajan, S.; Ritz, J. B lymphocytes from patients with chronic lymphocytic leukemia contain signal transducer and activator of transcription (STAT) 1 and STAT3 constitutively phosphorylated on serine residues. J. Clin. Investig. 1997, 100, 3140–3148. [Google Scholar] [CrossRef]
- Hazan-Halevy, I.; Harris, D.; Liu, Z.; Liu, J.; Li, P.; Chen, X.; Shanker, S.; Ferrajoli, A.; Keating, M.J.; Estrov, Z. STAT3 is constitutively phosphorylated on serine 727 residues, binds DNA, and activates transcription in CLL cells. Blood 2010, 115, 2852–2863. [Google Scholar] [CrossRef]
- Tolomeo, M.; Cavalli, A.; Cascio, A. STAT1 and Its Crucial Role in the Control of Viral Infections. Int. J. Mol. Sci. 2022, 23, 4095. [Google Scholar] [CrossRef]
- Battle, T.E.; Lynch, R.A.; Frank, D.A. Signal transducer and activator of transcription 1 activation in endothelial cells is a negative regulator of angiogenesis. Cancer Res. 2006, 66, 3649–3657. [Google Scholar] [CrossRef]
- Frank, D.A.; Mahajan, S.; Ritz, J. Fludarabine-induced immunosuppression is associated with inhibition of STAT1 signaling. Nat. Med. 1999, 5, 444–447. [Google Scholar] [CrossRef]
- Lynch, R.A.; Etchin, J.; Battle, T.E.; Frank, D.A. A small-molecule enhancer of signal transducer and activator of transcription 1 transcriptional activity accentuates the antiproliferative effects of IFN-gamma in human cancer cells. Cancer Res. 2007, 67, 1254–1261. [Google Scholar] [CrossRef]
- Alvarez, J.V.; Febbo, P.G.; Ramaswamy, S.; Loda, M.; Richardson, A.; Frank, D.A. Identification of a genetic signature of activated signal transducer and activator of transcription 3 in human tumors. Cancer Res. 2005, 65, 5054–5062. [Google Scholar] [CrossRef]
- Lamb, J. The Connectivity Map: A new tool for biomedical research. Nat. Rev. Cancer 2007, 7, 54–60. [Google Scholar] [CrossRef]
- Lamb, J.; Crawford, E.D.; Peck, D.; Modell, J.W.; Blat, I.C.; Wrobel, M.J.; Lerner, J.; Brunet, J.-P.; Subramanian, A.; Ross, K.N.; et al. The Connectivity Map: Using gene-expression signatures to connect small molecules, genes, and disease. Science 2006, 313, 1929–1935. [Google Scholar] [CrossRef]
- Hughes, W.T. The Role of Atovaquone Tablets in Treating Pneumocystis carinii Pneumonia. JAIDS J. Acquir. Immune Defic. Syndr. 1995, 8, 247. [Google Scholar] [CrossRef]
- Lv, Z.; Yan, X.; Lu, L.; Su, C.; He, Y. Atovaquone enhances doxorubicin’s efficacy via inhibiting mitochondrial respiration and STAT3 in aggressive thyroid cancer. J. Bioenerg. Biomembr. 2018, 50, 263–270. [Google Scholar] [CrossRef]
- Stevens, A.M.; Schafer, E.S.; Li, M.; Terrell, M.; Rashid, R.; Paek, H.; Bernhardt, M.B.; Weisnicht, A.; Smith, W.T.; Keogh, N.J.; et al. Repurposing Atovaquone as a Therapeutic against Acute Myeloid Leukemia (AML): Combination with Conventional Chemotherapy Is Feasible and Well Tolerated. Cancers 2023, 15, 1344. [Google Scholar] [CrossRef]
- Bashraheel, S.S.; Domling, A.; Goda, S.K. Update on targeted cancer therapies, single or in combination, and their fine tuning for precision medicine. Biomed. Pharmacother. Biomedecine Pharmacother. 2020, 125, 110009. [Google Scholar] [CrossRef]
- Siddiquee, K.A.Z.; Turkson, J. STAT3 as a target for inducing apoptosis in solid and hematological tumors. Cell Res. 2008, 18, 254–267. [Google Scholar] [CrossRef]
- Jin, N.; Xia, Y.; Gao, Q. Combined PARP inhibitors and small molecular inhibitors in solid tumor treatment (Review). Int. J. Oncol. 2023, 62, 28. [Google Scholar] [CrossRef]
- Chen, L.; Deng, H.; Cui, H.; Fang, J.; Zuo, Z.; Deng, J.; Li, Y.; Wang, X.; Zhao, L. Inflammatory responses and inflammation-associated diseases in organs. Oncotarget 2017, 9, 7204–7218. [Google Scholar] [CrossRef]
- Megha, K.B.; Joseph, X.; Akhil, V.; Mohanan, P.V. Cascade of immune mechanism and consequences of inflammatory disorders. Phytomedicine 2021, 91, 153712. [Google Scholar] [CrossRef] [PubMed]
- Wang, W.; Burton, F.; Herter, S.; Codarri Deak, L.; Klein, C.; Frank, D. Pharmacologic Inhibitors of STAT3 or BCL6 Transcriptional Function Sensitize Lymphoma Cells to the Novel PD-1 Cis-Targeted PD1-IL2v Immunocytokine in a Murine Model. Blood 2022, 140, 8835–8836. [Google Scholar] [CrossRef]
Methods | Preclinical Models | Expense | Advantage | Disadvantage |
---|---|---|---|---|
In vitro | Immortalized cell lines | Low | Can be easily maintained and expanded | Genetic instability and the occurrence of clonal selection |
Primary 2D cultures | Low | High take rate, amenable to genetic manipulation | Inability to reflect the histological nature | |
3D organoids | Moderate | Useful to study the interactions between different cell populations | Do not fully reproduce the complexity, lower sensitivity of cells | |
In vivo | Drosophila melanogaster | Low | Gives insight into asymmetric division. Genetic similarity with humans | Rudimentary hematopoietic systems and different lymphatic system |
Zebrafish | Moderate | Rapid development, chemical screening, amenable genetics, and fitness for in vivo imaging | Difficulty in the examination of fixed tissue, low tumor incidence | |
Patient-derived xenografts | Expensive | Conservation of a stromal compartment, tumor tissue expansion | Lack of a functional immune environment in PDX, prolonged time needed for model establishment and expansion compared to organoids | |
Carcinogen-induced mouse models | Expensive | Suitability to study effects of carcinogenic and genetic factors in tumorigenesis | Extended time needed to develop full-fledged carcinomas | |
Genetically engineered mouse models | Expensive | Closely recapitulate the heterogeneous landscape of genomic alterations in human primary tumors | Only a fraction of mutations drive tumorigenesis by affecting oncogenes or tumor suppressor genes | |
Pig cancer models | Expensive | Efficiently represent the progression and development of cancer in humans | Biosafety issues, larger housing requirements, longer generation intervals, and fewer genomic tools |
Type | Agent | Target | Cancer Type | ClinicalTrial.gov Identifier | Phase | References |
---|---|---|---|---|---|---|
Small molecules | Silibinin | STAT3 | Endometrial carcinoma | Preclinical | [147] | |
SD-36 | STAT3 | Acute myeloid leukemia and anaplastic large-cell lymphoma | Preclinical | [121] | ||
BP-1-102 | STAT3 | Acute lymphoblastic leukemia | Preclinical | [148] | ||
LLL12 | STAT3 | Ovarian cancer | Preclinical | [149] | ||
Pyrimethamine | STAT3 | Chronic lymphocytic leukemia | NCT01066663 | Phase 1/2 | [150] | |
OPB-51602 | STAT3 | Nasopharyngeal carcinoma | NCT01184807 | Phase 1 | [151] | |
N4 | STAT3 | Pancreatic cancer | Preclinical | [139] | ||
Atovaquone | STAT3 | Non-small cell lung cancer | NCT02628080 | Phase 1 | [152] | |
STAT3 | Acute myeloid leukemia | Preclinical | [153] | |||
Trichothecin | STAT3 | Colorectal Cancer | Preclinical | [154] | ||
SDL-1 | STAT3 | Gastric cancer | Preclinical | [155] | ||
AK-2292 | STAT5 | Chronic myeloid leukemia | Preclinical | [156] | ||
Oligonucleotides | Danvatirsen | STAT3 | Diffuse large B cell lymphoma | NCT03527147 | Phase 1 | [157] |
STAT3 | Myelodysplastic syndromes, acute myeloid leukemia | NCT05986240 | Phase 1 | [158] | ||
Double-stranded minicircles | STAT3 | Triple-negative breast cancer | Preclinical | [159] | ||
Peptides | OPB-31121 | STAT3 | Hepatocellular carcinoma | NCT01406574 | Phase 1/2 | [157] |
PS-acet.-STAT3 peptide | STAT3 | Melanoma | Preclinical | [160] |
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Wang, W.; Lopez McDonald, M.C.; Hariprasad, R.; Hamilton, T.; Frank, D.A. Oncogenic STAT Transcription Factors as Targets for Cancer Therapy: Innovative Strategies and Clinical Translation. Cancers 2024, 16, 1387. https://doi.org/10.3390/cancers16071387
Wang W, Lopez McDonald MC, Hariprasad R, Hamilton T, Frank DA. Oncogenic STAT Transcription Factors as Targets for Cancer Therapy: Innovative Strategies and Clinical Translation. Cancers. 2024; 16(7):1387. https://doi.org/10.3390/cancers16071387
Chicago/Turabian StyleWang, Weiyuan, Melanie Cristina Lopez McDonald, Rajashree Hariprasad, Tiara Hamilton, and David A. Frank. 2024. "Oncogenic STAT Transcription Factors as Targets for Cancer Therapy: Innovative Strategies and Clinical Translation" Cancers 16, no. 7: 1387. https://doi.org/10.3390/cancers16071387