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STAT3 Activation as a Predictive Biomarker for Ruxolitinib Response in Head and Neck Cancer
Zoya Qureshy1, Hua Li1, Yan Zeng1
1Department of Otolaryngology-Head and Neck Surgery, University of California San Francisco, San Francisco, California.
Purpose:
Increased 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 Design:
HNSCC 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.
Results:
Ruxolitinib 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.
Conclusions:
Ruxolitinib 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.
Insights
Ruxolitinib, a JAK1/2 inhibitor, demonstrated anticancer effects in head and neck squamous cell carcinoma (HNSCC) models. Baseline STAT3 levels may predict patient response to this targeted therapy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Increased Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) pathway activity is implicated in head and neck squamous cell carcinoma (HNSCC) progression.
- JAKs are potential therapeutic targets for HNSCC treatment.
Purpose of the Study:
- To investigate the anticancer effects of ruxolitinib, a JAK1/2 inhibitor, in HNSCC preclinical models.
- To evaluate ruxolitinib's impact on STAT3 activation and tumor growth in HNSCC.
Main Methods:
- Assessed ruxolitinib's effects on HNSCC cell lines, including STAT3 activation, growth, and colony formation.
- Utilized patient-derived xenografts (PDXs) from HNSCC patients treated with neoadjuvant ruxolitinib to assess in vivo efficacy and STAT3 inhibition.
Main Results:
- Ruxolitinib inhibited STAT3 activation, cellular growth, and colony formation in HNSCC cell lines.
- Ruxolitinib significantly inhibited tumor growth in HNSCC xenograft models.
- Responses in PDXs correlated with clinical outcomes, with lower baseline STAT3 activation in responsive tumors.
Conclusions:
- Ruxolitinib shows significant antitumor activity in preclinical HNSCC models.
- Baseline STAT3 activation levels (pSTAT3 or total STAT3) could serve as predictive biomarkers for ruxolitinib response in HNSCC patients.
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