Targeting the interleukin-6/JAK/STAT pathway in human malignancies

Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, NY 10021, USA.
Journal of Clinical Oncology (Impact Factor: 18.43). 02/2012; 30(9):1005-14. DOI: 10.1200/JCO.2010.31.8907
Source: PubMed

ABSTRACT The Janus kinase/signal transducer and activator of transcription (Jak/Stat) pathway was discovered 20 years ago as a mediator of cytokine signaling. Since this time, more than 2,500 articles have been published demonstrating the importance of this pathway in virtually all malignancies. Although there are dozens of cytokines and cytokine receptors, four Jaks, and seven Stats, it seems that interleukin-6-mediated activation of Stat3 is a principal pathway implicated in promoting tumorigenesis. This transcription factor regulates the expression of numerous critical mediators of tumor formation and metastatic progression. This review will examine the relative importance and function of this pathway in nonmalignant conditions as well as malignancies (including tumor intrinsic and extrinsic), the influence of other Stats, the development of inhibitors to this pathway, and the potential role of inhibitors in controlling or eradicating cancers.

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    • "IL-6 may also have an essential role in the growth and differentiation of malignant tumors (Mandal et al., 2014; Zarogoulidis et al., 2013). IL-6 is a multifunctional cytokine of Th2 type which has both, pro-inflammatory and antiinflammatory cytokine activities (Sansone and Bromberg, 2012). It is a glycoprotein which consists of 184 amino acids and has a molecular weight of 26 kDa (Guo et al., 2012). "
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    ABSTRACT: Interleukin-6 (IL-6) encodes a cytokine protein, which causes inflammation, maintains immune homeostasis and plays an essential role in oral pathogenesis. The aim of this study was to evaluate the association between IL-6 (- 174 and - 572) G/C promoter gene polymorphisms and risk of OSCC among Indians. Single nucleotide polymorphism in IL-6 genes was genotyped in OSCC patients and healthy controls by PCR-RFLP method. Genotype and allele frequencies were analyzed by chi-square test and strength of associations by odds ratio with 95% confidence intervals. Frequency distribution of IL-6 (- 174) G/C gene polymorphism was significantly associated with OSCC patients in comparison to healthy controls (OR: 0.541, CI: 0.356-0.822; p: 0.004. However, frequency of IL-6 (- 572) G/C gene polymorphism was not significantly associated with OSCC patients (p > 0.05). The genotype GC and allele C of IL-6 (- 174) G/C gene polymorphism play a significant role in OSCC susceptibility.
    Meta Gene 06/2015; 4. DOI:10.1016/j.mgene.2015.03.002
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    • "STAT3 is activated downstream of several kinases including JAKs. While there is little evidence to date to support a critical function of JAKs in HNSCC, cumulative evidence implicates STAT3 activation in HNSCC progression [2] "
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    ABSTRACT: Aberrant activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) 3 has been implicated in cell proliferation and survival of many cancers including head and neck squamous cell carcinoma (HNSCC). AZD1480, an orally active pharmacologic inhibitor of JAK1/JAK2, has been tested in several cancer models. In the present study, the in vitro and in vivo effects of AZD1480 were evaluated in HNSCC preclinical models to test the potential use of JAK kinase inhibition for HNSCC therapy. AZD1480 treatment decreased HNSCC proliferation in HNSCC cell lines with half maximal effective concentration (EC50) values ranging from 0.9 to 4 μM in conjunction with reduction of pSTAT3Tyr705 expression. In vivo antitumor efficacy of AZD1480 was demonstrated in patient-derived xenograft (PDX) models derived from two independent HNSCC tumors. Oral administration of AZD1480 reduced tumor growth in conjunction with decreased pSTAT3Tyr705 expression that was observed in both PDX models. These findings suggest that the JAK1/2 inhibitors abrogate STAT3 signaling and may be effective in HNSCC treatment approaches. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Neoplasia (New York, N.Y.) 03/2015; 3(3). DOI:10.1016/j.neo.2015.01.003 · 4.25 Impact Factor
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    • "Comparable mutations have not been well studied in breast cancer. However STAT1, STAT3, and STAT5 are often constitutively phosphorylated, seemingly due to elevated levels of cytokines and receptors.152 Preclinical studies showed that the interleukin-6/JAK2/STAT3 pathway is preferentially activated in basal-like breast cancer cells, and inhibition of JAK2 with NBP-BSK805 hinders the growth of patient-derived breast tumor xenografts.153 "
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    ABSTRACT: Breast cancers expressing estrogen receptor α, progesterone receptor, or the human epidermal growth factor receptor 2 (HER2) proto-oncogene account for approximately 90% of cases, and treatment with antiestrogens and HER2-targeted agents has resulted in drastically improved survival in many of these patients. However, de novo or acquired resistance to antiestrogen and HER2-targeted therapies is common, and many tumors will recur or progress despite these treatments. Additionally, the remaining 10% of breast tumors are negative for estrogen receptor α, progesterone receptor, and HER2 ("triple-negative"), and a clinically proven tumor-specific drug target for this group has not yet been identified. Therefore, the identification of new therapeutic targets in breast cancer is of vital clinical importance. Preclinical studies elucidating the mechanisms driving resistance to standard therapies have identified promising targets including cyclin-dependent kinase 4/6, phosphoinositide 3-kinase, poly adenosine diphosphate-ribose polymerase, Src, and histone deacetylase. Herein, we discuss the clinical potential and status of new therapeutic targets in breast cancer.
    Pharmacogenomics and Personalized Medicine 08/2014; 7(1):203-15. DOI:10.2147/PGPM.S52762
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