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Overview of the STAT-3 signaling pathway in cancer and the development of specific inhibitors.

ABSTRACT: Signal transducer and activator of transcription (STAT) proteins represent novel therapeutic targets for the treatment of cancer. In particular, STAT-3 serves critical roles in several cellular processes, including the cell cycle, cell proliferation, cellular apoptosis and tumorigenesis. Persistent activation of STAT-3 has been reported in a variety of cancer types, and a poor prognosis of cancer may be associated with the phosphorylation level of STAT-3. Furthermore, elevated STAT-3 activity has been demonstrated in a variety of mammalian cancers, both in vitro and in vivo. This indicates that STAT-3 serves an important role in the progression of numerous cancer types. A significant obstacle in developing STAT-3 inhibitors is the demonstration of the antitumor efficacy in in vivo systems and the lack of animal models for human tumors. Therefore, it is crucial to determine whether available STAT-3 inhibitors are suitable for clinical trials. Moreover, further preclinical studies are necessary to focus on the impact of STAT-3 inhibitors on tumor cells. When considering STAT-3 hyper-activation in human cancer, selective targeting to these proteins holds promise for significant advancement in cancer treatment. In the present study, advances in our knowledge of the structure of STAT-3 protein and its regulatory mechanisms are summarized. Moreover, the STAT-3 signaling pathway and its critical role in malignancy are discussed, in addition to the development of STAT-3 inhibitors in various cancer types.

SUBMITTER: Gu Y

PROVIDER: S-EPMC7068531 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Overview of the STAT-3 signaling pathway in cancer and the development of specific inhibitors.

Gu Yuchen Y Mohammad Imran Shair IS Liu Zhe Z

Oncology letters 20200213 4

Signal transducer and activator of transcription (STAT) proteins represent novel therapeutic targets for the treatment of cancer. In particular, STAT-3 serves critical roles in several cellular processes, including the cell cycle, cell proliferation, cellular apoptosis and tumorigenesis. Persistent activation of STAT-3 has been reported in a variety of cancer types, and a poor prognosis of cancer may be associated with the phosphorylation level of STAT-3. Furthermore, elevated STAT-3 activity ha ...[more]

PMID: 32218808

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Project description:Dysregulated cell division, which leads to aberrant cell proliferation, is one of the key hallmarks of cancer. Therefore, therapeutic targets that block cell division would be effective for cancer treatment. Cell division is mainly controlled by a complex composed of cyclin and cyclin dependent kinases (CDKs). To date, the CDK inhibitors (CDKIs), specifically the ones that block the enzyme activity of CDK4 and CDK6 (CDK4/6), have been approved by FDA for the treatment of metastatic hormone receptor positive breast cancer. However, due to the non-selectivity and significant toxicity, most of the first generation CDK inhibitors (so called pan-CDK inhibitors that target several CDKs), have not been approved for clinical application. Despite this, great efforts and progress have been made to enable pan-CDK inhibitors application in the clinical setting. Notably, the development of combination therapy strategies in recent years has made it possible to reduce the toxicity and side effects of pan-CDK inhibitors. Thus, as a combination therapy approach, pan-CDK inhibitors regain great potential in clinical application. In this review, we introduced the CDK family members and discussed their major functions in cell cycle controlling. Then, we summarized the research progress regarding CDK inhibitors, especially those other than CDK4/6 inhibitors. We reviewed first-generation pan-CDKIs Flavopiridol and Roscovitine, and second-generation CDKIs Dinaciclib, P276-00, AT7519, TG02, Roniciclib, RGB-286638 by focusing on their developing stages, clinical trials and targeting cancers. The specific CDKIs, which targets to increase specificity and decrease the side effects, were also discussed. These CDKIs include CDK4/6, CDK7, CDK9, and CDK12/13 inhibitors. Finally, the efficacy and discrepancy of combination therapy with CDK inhibitors and PD1/PDL1 antibodies were analyzed, which might give insights into the development of promising strategy for cancer treatment.

Dataset Information

Overview of the STAT-3 signaling pathway in cancer and the development of specific inhibitors.

Publications

Overview of the STAT-3 signaling pathway in cancer and the development of specific inhibitors.

Similar Datasets

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