STAT3 Activation as a Predictive Biomarker for Ruxolitinib Response in Head and Neck Cancer.
STAT3 Activation as a Predictive Biomarker for Ruxolitinib Response in Head and Neck Cancer.
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DOI：
10.1158/1078-0432.ccr-22-0744
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发表时间：
2022-11-01
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STAT3活性增加与头颈部鳞状细胞癌（HNSCC）的进展相关。STAT3的上游激活因子，如JAKs，是包括HNSCC在内的实体瘤治疗的潜在靶点。在这项研究中，我们在HNSCC临床前模型中研究了鲁索替尼（一种临床用JAK1/2抑制剂）的抗癌作用，这些模型包括来自机会窗试验中接受治疗的患者的人源肿瘤异种移植模型（PDXs）。
用鲁索替尼处理HNSCC细胞系，并评估其对活化的STAT3水平、细胞生长和集落形成的影响。从在临床试验中接受短期新辅助鲁索替尼治疗的HNSCC患者中构建PDXs。评估鲁索替尼对肿瘤生长和STAT3激活的影响。
鲁索替尼抑制HNSCC细胞系中STAT3的激活、细胞生长和集落形成。与溶媒处理的对照组相比，用鲁索替尼治疗携带HNSCC细胞系来源的异种移植物的小鼠显著抑制肿瘤生长。来自临床试验患者的HNSCC PDXs的反应反映了在新辅助治疗环境中观察到的反应。与来自鲁索替尼治疗后疾病进展且鲁索替尼治疗对STAT3激活影响极小的患者的PDX相比，来自鲁索替尼治疗后疾病稳定的患者的PDX中基线活化STAT3（pSTAT3）和总STAT3水平较低，且鲁索替尼抑制STAT3激活。
鲁索替尼在HNSCC临床前模型中表现出抗肿瘤作用。肿瘤中的基线pSTAT3或总STAT3水平可作为预测性生物标志物，用于识别最有可能对鲁索替尼有反应的患者。
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 anti-cancer effects of ruxolitinib, a clinical JAK1/2 inhibitor, in HNSCC preclinical models including patient-derived xenografts (PDXs) from patients treated on a window-of-opportunity trial. 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 HNSCC patients who received a brief course of neoadjuvant ruxolitinib on a clinical trial. The impact of ruxolitinib on tumor growth and STAT3 activation was assessed. Ruxolitinib inhibited STAT3 activation, cellular growth and colony formation of HNSCC cell lines. Ruxolitinib treatment of mice bearing a 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 to a PDX from a patient whose disease progressed on ruxolitinib and where ruxolitinib treatment had minimal impact on STAT3 activation. 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.