1. STAT3 Activation as a Predictive Biomarker for Ruxolitinib Response in Head and Neck Cancer.
- Author
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Qureshy, Zoya, Li, Hua, Zeng, Yan, Rivera, Jose, Cheng, Ning, Peterson, Christopher N, Kim, Mi-Ok, Ryan, William R, Ha, Patrick K, Bauman, Julie E, Wang, Steven J, Long, Steven R, Johnson, Daniel E, and Grandis, Jennifer R
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Dental/Oral and Craniofacial Disease ,Rare Diseases ,Orphan Drug ,Clinical Research ,Good Health and Well Being ,Humans ,Mice ,Animals ,Squamous Cell Carcinoma of Head and Neck ,Carcinoma ,Squamous Cell ,Xenograft Model Antitumor Assays ,Head and Neck Neoplasms ,STAT3 Transcription Factor ,Biomarkers ,Cell Line ,Tumor ,Oncology & Carcinogenesis ,Clinical sciences ,Oncology and carcinogenesis - Abstract
PurposeIncreased activity of STAT3 is associated with progression of head and neck squamous cell carcinoma (HNSCC). Upstream activators of STAT3, such as JAKs, represent potential targets for therapy of solid tumors, including HNSCC. In this study, we investigated the anticancer effects of ruxolitinib, a clinical JAK1/2 inhibitor, in HNSCC preclinical models, including patient-derived xenografts (PDX) from patients treated on a window-of-opportunity trial.Experimental designHNSCC cell lines were treated with ruxolitinib, and the impact on activated STAT3 levels, cell growth, and colony formation was assessed. PDXs were generated from patients with HNSCC who received a brief course of neoadjuvant ruxolitinib on a clinical trial. The impact of ruxolitinib on tumor growth and STAT3 activation was assessed.ResultsRuxolitinib inhibited STAT3 activation, cellular growth, and colony formation of HNSCC cell lines. Ruxolitinib treatment of mice bearing an HNSCC cell line-derived xenograft significantly inhibited tumor growth compared with vehicle-treated controls. The response of HNSCC PDXs derived from patients on the clinical trial mirrored the responses seen in the neoadjuvant setting. Baseline active STAT3 (pSTAT3) and total STAT3 levels were lower, and ruxolitinib inhibited STAT3 activation in a PDX from a patient whose disease was stable on ruxolitinib, compared with a PDX from a patient whose disease progressed on ruxolitinib and where ruxolitinib treatment had minimal impact on STAT3 activation.ConclusionsRuxolitinib exhibits antitumor effects in HNSCC preclinical models. Baseline pSTAT3 or total STAT3 levels in the tumor may serve as predictive biomarkers to identify patients most likely to respond to ruxolitinib.
- Published
- 2022