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

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.

• Authors: Malabika Sen, Netanya I Pollock, John Black, Kara A DeGrave, Sarah Wheeler, Maria L Freilino, Sonali Joyce, Vivian W Y Lui, Yan Zeng, Simion I Chiosea, Jennifer R Grandis
• Journal: Neoplasia (New York, N.Y.) (Neoplasia) Vol. 17 Issue 3 Pg. 256-64 (Mar 2015) ISSN: 1476-5586 [Electronic] United States
• PMID: 25810010 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• AZD 1480
• Antineoplastic Agents
• Protein Kinase Inhibitors
• Pyrazoles
• Pyrimidines
• RNA, Messenger
• STAT3 Transcription Factor
• Janus Kinase 1
• Janus Kinase 2
• Janus Kinases

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Carcinoma, Squamous Cell (genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Gene Dosage
• Gene Expression
• Head and Neck Neoplasms (genetics, metabolism, pathology)
• Humans
• Janus Kinase 1 (antagonists & inhibitors, genetics, metabolism)
• Janus Kinase 2 (antagonists & inhibitors, genetics, metabolism)
• Janus Kinases (antagonists & inhibitors, genetics, metabolism)
• Mice
• Phosphorylation
• Protein Kinase Inhibitors (pharmacology)
• Pyrazoles (pharmacology)
• Pyrimidines (pharmacology)
• RNA, Messenger (genetics)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (drug effects)
• Squamous Cell Carcinoma of Head and Neck
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays