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JAK激酶抑制可消除STAT3激活以及头颈部鳞状细胞癌肿瘤生长。

JAK kinase inhibition abrogates STAT3 activation and head and neck squamous cell carcinoma tumor growth.

作者信息

Sen Malabika, Pollock Netanya I, Black John, DeGrave Kara A, Wheeler Sarah, Freilino Maria L, Joyce Sonali, Lui Vivian W Y, Zeng Yan, Chiosea Simion I, Grandis Jennifer R

机构信息

Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

出版信息

Neoplasia. 2015 Mar;17(3):256-64. doi: 10.1016/j.neo.2015.01.003.

DOI:10.1016/j.neo.2015.01.003
PMID:25810010
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4372647/
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 pSTAT3(Tyr705) 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 pSTAT3(Tyr705) 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.

摘要

Janus激酶（JAK）/信号转导子和转录激活子（STAT）3的异常激活与包括头颈部鳞状细胞癌（HNSCC）在内的多种癌症的细胞增殖和存活有关。AZD1480是一种口服活性JAK1/JAK2药理抑制剂，已在多种癌症模型中进行了测试。在本研究中，在HNSCC临床前模型中评估了AZD1480的体外和体内作用，以测试JAK激酶抑制在HNSCC治疗中的潜在用途。AZD1480处理降低了HNSCC细胞系中HNSCC的增殖，半数最大有效浓度（EC50）值范围为0.9至4 μM，同时降低了pSTAT3（Tyr705）的表达。AZD1480在源自两个独立HNSCC肿瘤的患者来源异种移植（PDX）模型中显示出体内抗肿瘤功效。口服AZD1480可减少肿瘤生长，同时降低两个PDX模型中观察到的pSTAT3（Tyr705）表达。这些发现表明，JAK1/2抑制剂可消除STAT3信号传导，可能对HNSCC治疗有效。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/18e3/4372647/d68a11724c0f/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/18e3/4372647/b04b8f1875a7/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/18e3/4372647/abd31cb9922e/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/18e3/4372647/a3d6c2d48171/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/18e3/4372647/da3124ea42ad/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/18e3/4372647/46829bd4620f/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/18e3/4372647/75c6e65c63a2/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/18e3/4372647/d68a11724c0f/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/18e3/4372647/b04b8f1875a7/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/18e3/4372647/abd31cb9922e/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/18e3/4372647/a3d6c2d48171/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/18e3/4372647/da3124ea42ad/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/18e3/4372647/46829bd4620f/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/18e3/4372647/75c6e65c63a2/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/18e3/4372647/d68a11724c0f/gr7.jpg

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[3]
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[3]
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[4]
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[5]
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[8]
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[9]
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[10]
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本文引用的文献

[1]
The Janus kinases inhibitor AZD1480 attenuates growth of small cell lung cancers in vitro and in vivo.

Clin Cancer Res. 2013-10-24

[2]
Nucleic acid-based approaches to STAT inhibition.

JAKSTAT. 2012-10-1

[3]
Pharmacologic inhibition of Jak2-Stat5 signaling By Jak2 inhibitor AZD1480 potently suppresses growth of both primary and castrate-resistant prostate cancer.

Clin Cancer Res. 2013-8-13

[4]
Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers.

Cancer Discov. 2013-4-25

[5]
Comprehensive review of JAK inhibitors in myeloproliferative neoplasms.

Ther Adv Hematol. 2013-2

[6]
A patient tumor transplant model of squamous cell cancer identifies PI3K inhibitors as candidate therapeutics in defined molecular bins.

Mol Oncol. 2013-4-4

[7]
Inhibition of STAT3 with orally active JAK inhibitor, AZD1480, decreases tumor growth in Neuroblastoma and Pediatric Sarcomas In vitro and In vivo.

Oncotarget. 2013-3

[8]
Development and characterization of HPV-positive and HPV-negative head and neck squamous cell carcinoma tumorgrafts.

Clin Cancer Res. 2012-12-18

[9]
AZD1480 blocks growth and tumorigenesis of RET- activated thyroid cancer cell lines.

PLoS One. 2012-10-2

[10]
The JAK inhibitor AZD1480 regulates proliferation and immunity in Hodgkin lymphoma.

Blood Cancer J. 2011-12-2

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