Jak Stat signaling and cancer: Opportunities, benefits and side effects of targeted inhibition.

The Activator Protein-1 (AP-1) transcription factor (TF) family, composed of a variety of members including c-JUN, c-FOS and ATF, is involved in mediating many biological processes such as proliferation, differentiation and cell death. Since their discovery, the role of AP-1 TFs in cancer development has been extensively analysed. Multiple in vitro and in vivo studies have highlighted the complexity of these TFs, mainly due to their cell-type specific homo- or hetero-dimerization resulting in diverse transcriptional response profiles. However, as a result of the increasing knowledge of the role of AP-1 TFs in disease, these TFs are being recognized as promising therapeutic targets for various malignancies. In this review, we focus on the impact of deregulated expression of AP-1 TFs in CD30-positive lymphomas including Classical Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma.

https://www.repository.cam.ac.uk/bitstream/1810/288664/3/Role_of_Activator_Protein-1.pdf

The Role of Activator Protein-1 (AP-1) Family Members in CD30-Positive Lymphomas

Natural killer (NK) cells are tightly regulated by the JAK–STAT signaling pathway and cannot survive in the absence of STAT5. We now report that STAT5-deficient NK cells can be rescued by overexpression of BCL2. Our experiments define STAT5 as a master regulator of NK-cell proliferation and lytic functions. Although NK cells are generally responsible for killing tumor cells, the rescued STAT5-deficient NK cells promote tumor formation by producing enhanced levels of the angiogenic factor VEGFA. The importance of VEGFA produced by NK cells was verified by experiments with a conditional knockout of VEGFA in NK cells. We show that STAT5 normally represses the transcription of VEGFA in NK cells, in both mice and humans. These findings reveal that STAT5-directed therapies may have negative effects: In addition to impairing NK-cell–mediated tumor surveillance, they may even promote tumor growth by enhancing angiogenesis.

Significance: The importance of the immune system in effective cancer treatment is widely recognized. We show that the new signal interceptors targeting the JAK–STAT5 pathway may have dangerous side effects that must be taken into account in clinical trials: inhibiting JAK–STAT5 has the potential to promote tumor growth by enhancing NK-cell–mediated angiogenesis. Cancer Discov; 6(4); 414–29. ©2016 AACR .

See related commentary by Ni and Cerwenka, [p. 347][1] .

This article is highlighted in the In This Issue feature, [p. 331][2]

 [1]: /lookup/volpage/6/347?iss=4
 [2]: /lookup/volpage/6/331?iss=4

https://cancerdiscovery.aacrjournals.org/content/candisc/early/2016/03/23/2159-8290.CD-15-0732.full.pdf

STAT5 Is a Key Regulator in NK Cells and Acts as a Molecular Switch from Tumor Surveillance to Tumor Promotion

The transcription factor STAT5 is an essential downstream mediator of many tyrosine kinases (TKs), particularly in hematopoietic cancers. STAT5 is activated by FLT3-ITD, which is a constitutively active TK driving the pathogenesis of acute myeloid leukemia (AML). Since STAT5 is a critical mediator of diverse malignant properties of AML cells, direct targeting of STAT5 is of significant clinical value. Here, we describe the development and preclinical evaluation of a novel, potent STAT5 SH2 domain inhibitor, AC-4-130, which can efficiently block pathological levels of STAT5 activity in AML. AC-4-130 directly binds to STAT5 and disrupts STAT5 activation, dimerization, nuclear translocation, and STAT5-dependent gene transcription. Notably, AC-4-130 substantially impaired the proliferation and clonogenic growth of human AML cell lines and primary FLT3-ITD+ AML patient cells in vitro and in vivo. Furthermore, AC-4-130 synergistically increased the cytotoxicity of the JAK1/2 inhibitor Ruxolitinib and the p300/pCAF inhibitor Garcinol. Overall, the synergistic effects of AC-4-130 with TK inhibitors (TKIs) as well as emerging treatment strategies provide new therapeutic opportunities for leukemia and potentially other cancers.

/pdf/pharmacologic-inhibition-of-stat5-in-acute-myeloid-leukemia-2z68ytvr6w.pdf

Pharmacologic inhibition of STAT5 in acute myeloid leukemia

https://www.exphem.org/article/S0301-472X(15)00215-5/pdf

Pathogenesis of myeloproliferative neoplasms

We herein report the design and synthesis of the first nanomolar binding inhibitor of STAT5 protein. Lead compound 13a, possessing a phosphotyrosyl-mimicking salicylic acid group, potently and selectively binds to STAT5 over STAT3, inhibits STAT5–SH2 domain complexation events in vitro, silences activated STAT5 in leukemic cells, as well as STAT5′s downstream transcriptional targets, including MYC and MCL1, and, as a result, leads to apoptosis. We believe 13a represents a useful probe for interrogating STAT5 function in cells as well as being a potential candidate for advanced preclinical trials.

Nanomolar-Potency Small Molecule Inhibitor of STAT5 Protein.

285 A nanomolar-potency small molecule inhibitor of the STAT5 protein

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Nanomolar-Potency Small Molecule Inhibitor of STAT5 Protein.

285 A nanomolar-potency small molecule inhibitor of the STAT5 protein