An update on investigational therapies that target STAT3 for the treatment of cancer

Santoni, Matteo; Miccini, Francesca; Cimadamore, Alessia; Piva, Francesco; Massari, Francesco; Cheng, Liang; López-Beltrán, Antonio; Montironi, Rodolfo; Battelli, Nicola

doi:10.1080/13543784.2021.1891222

Cited by 19 publications

(17 citation statements)

References 72 publications

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“…In recent years, OC treatment mainly focuses on targeted therapy and surgery. Accompanied by in-depth research on the pathogenesis of OC, great progress has been made in OC therapies [ 15 ]. However, despite continuous improvement in therapy, the overall 5-year survival rate of OC patients at advanced stages was less than 50% [ 16 ].…”

Section: Discussionmentioning

confidence: 99%

Downregulation of cell division cycle-associated protein 7 (CDCA7) suppresses cell proliferation, arrests cell cycle of ovarian cancer, and restrains angiogenesis by modulating enhancer of zeste homolog 2 (EZH2) expression

2021

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Section: Discussionmentioning

confidence: 99%

Downregulation of cell division cycle-associated protein 7 (CDCA7) suppresses cell proliferation, arrests cell cycle of ovarian cancer, and restrains angiogenesis by modulating enhancer of zeste homolog 2 (EZH2) expression

2021

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“…STAT3, which has a relative molecular weight of 92 kDa, consists of approximately 770 amino acids and includes six functional domains: the N-terminal domain, coiled-coil domain, DNA binding domain, C-terminal transactivation domain, linker domain, and Src homology 2 (SH2) domain. Each domain which plays a different role in signal transduction and the activation of gene transcription [ 26 , 27 ]. The N-terminal domain is involved in STAT3 dimer nuclear translocation, synergistic DNA binding, protein–protein interactions to form various dimer complexes, and subsequent negative regulatory processes [ 27 ].…”

Section: Structure and Signalling Cascades Of Stat3mentioning

confidence: 99%

STAT3-mediated osteogenesis and osteoclastogenesis in osteoporosis

Hou

Tian

2022

Cell Commun Signal

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Osteoporosis is a common skeletal disease with marked bone loss, deterioration of the bone microstructure and bone fragility. An abnormal bone remodelling cycle with relatively increased bone resorption is the crucial pathophysiological mechanism. Bone remodelling is predominantly controlled by osteoblasts and osteoclasts, which are specialized cell types that are regulated by a variety of osteogenic and osteoclastic factors, including cytokines expressed within the bone microenvironment under local or systemic inflammatory conditions. Signal transducer and activator of transcription 3 (STAT3) plays a prominent role in the communication between cytokines and kinases by binding downstream gene promotors and is involved in a wide range of biological or pathological processes. Emerging evidence suggests that STAT3 and its network participate in bone remodelling and the development of osteoporosis, and this factor may be a potent target for osteoporosis treatment. This review focuses on the role and molecular mechanism of the STAT3 signalling pathway in osteogenesis, osteoclastogenesis and osteoporosis, particularly the bone-related cytokines that regulate the osteoblastic differentiation of bone marrow stromal cells and the osteoclastic differentiation of bone marrow macrophages by initiating STAT3 signalling. This review also examines the cellular interactions among immune cells, haematopoietic cells and osteoblastic/osteoclastic cells.

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“…Constitutive activation of STAT3 has been demonstrated to be an oncogenic feature in numerous tumours, including melanoma 29–31 . The regulatory effect of EEF2K on STAT3 was contradictory in two previous studies.…”

Section: Discussionmentioning

confidence: 93%

EEF2K silencing inhibits tumour progression through repressing SPP1 and synergises with BET inhibitors in melanoma

Deng

Zeng

et al. 2022

Clinical & Translational Med

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Background Despite the remarkable breakthroughs achieved in the management of metastatic melanoma using immunotherapy and targeted therapies, long‐term clinical efficacy is often compromised due to dose‐limiting toxicity and innate or acquired resistance. Therefore, it is of vital importance to further explore the molecular mechanisms underlying melanoma progression and identify new targeted therapeutic approaches. Methods The function of eukaryotic elongation factor‐2 kinase (EEF2K) in melanoma were investigated in vitro and in vivo. RNA‐seq and chromatin immunoprecipitation (ChIP) assay were undertaken to explore the mechanisms. The antitumor effect of bromodomain and extra terminal domain (BET) inhibitors combined with cytarabine were assessed in melanoma both in vitro and in vivo. Results EEF2K silencing markedly attenuated the malignant phenotypes of melanoma cells, including proliferation, migration, invasion and metastasis. In contrast, EEF2K overexpression promoted melanoma cell proliferation, migration and invasion. Mechanistically, we demonstrated that EEF2K upregulates the phosphorylation of STAT3 (p‐STAT3) at Tyr705, which binds to the promoter region of SPP1 and enhances its transcription, thus facilitating melanoma progression. Transfection‐induced re‐expression of SPP1 partly negated the inhibitory effect of EEF2K silencing on melanoma, whereas inhibition of SPP1 or STAT3 significantly abolished the efficacy of EEF2K on melanoma cells. Intriguingly, EEF2K silencing combined with BET inhibitor treatment further inhibited cell proliferation and promoted apoptosis in melanoma. We further screened the US FDA‐approved antitumour drug library and identified cytarabine as a potential clinically applicable EEF2K inhibitor that could synergise with BET inhibitors in melanoma treatment. Conclusion EEF2K/p‐STAT3/SPP1 may be a novel oncogenic pathway in melanoma progression, which could be a target for novel combination therapy for melanoma.

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An update on investigational therapies that target STAT3 for the treatment of cancer

Cited by 19 publications

References 72 publications

Downregulation of cell division cycle-associated protein 7 (CDCA7) suppresses cell proliferation, arrests cell cycle of ovarian cancer, and restrains angiogenesis by modulating enhancer of zeste homolog 2 (EZH2) expression

Downregulation of cell division cycle-associated protein 7 (CDCA7) suppresses cell proliferation, arrests cell cycle of ovarian cancer, and restrains angiogenesis by modulating enhancer of zeste homolog 2 (EZH2) expression

STAT3-mediated osteogenesis and osteoclastogenesis in osteoporosis

EEF2K silencing inhibits tumour progression through repressing SPP1 and synergises with BET inhibitors in melanoma

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