title: 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: Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors: Malabika
authors: M
authors: Sen
authors: Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors: Netanya I
authors: NI
authors: Pollock
authors: Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors: John
authors: J
authors: Black
authors: Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors: Kara A
authors: KA
authors: DeGrave
authors: Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors: Sarah
authors: S
authors: Wheeler
authors: Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors: Maria L
authors: ML
authors: Freilino
authors: Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors: Sonali
authors: S
authors: Joyce
authors: Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors: Vivian W Y
authors: VW
authors: Lui
authors: Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors: Yan
authors: Y
authors: Zeng
authors: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors: Simion I
authors: SI
authors: Chiosea
authors: Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Electronic address: jgrandis@pitt.edu.
authors: Jennifer R
authors: JR
authors: Grandis
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D018628:Gene Dosage; D015870:Gene Expression; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D053612:Janus Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000077195:Squamous Cell Carcinoma of Head and Neck; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C545606:AZD 1480; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053612:Janus Kinases