Resistance to paclitaxel poses a major obstacle in esophageal squamous cell carcinoma (ESCC) treatment. A better understanding of the mechanisms underlying paclitaxel resistance could help identify prognostic biomarkers and improved therapeutic strategies. In this study, we established a patient-derived xenograft (PDX) model of acquired paclitaxel resistance and used RNA-sequencing to identify galectin-1, encoded by LGALS1, as a key mediator of resistance. Integrative analysis of clinical data and physiological studies indicated that serum galectin-1 levels were elevated in resistant patients and correlated with treatment outcomes before and during taxane therapy. Importantly, exposing cells to serum from resistant patients resulted in increased paclitaxel resistance compared to serum from sensitive patients, which was closely associated with galectin-1 concentrations in the serum. The specific clearance of galectin-1 from resistant patient serum significantly restored paclitaxel sensitivity, and inhibiting galectin-1, through knockdown or the pharmacologic inhibitor OTX008, increased sensitivity to paclitaxel. Galectin-1 inhibition reduced the activity of β-catenin, thereby inhibiting stem cell properties induced by the Wnt/β-catenin pathway. Furthermore, galectin-1 regulated MDR1 transcription through increased nuclear accumulation of β-catenin, thus increasing resistance to paclitaxel. Combining OTX008 with clinical taxane formulations effectively reversed paclitaxel resistance in vitro and in vivo. Elevated galectin-1 levels thus serve as an indicator of response to paclitaxel therapy in ESCC, offering a therapeutic intervention strategy to overcome drug resistance.

中文翻译：

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靶向半乳糖凝集素-1 克服了食管鳞状细胞癌中的紫杉醇耐药性


对紫杉醇的耐药性是食管鳞状细胞癌 （ESCC） 治疗的主要障碍。更好地了解紫杉醇耐药的机制有助于确定预后生物标志物和改进治疗策略。在这项研究中，我们建立了获得性紫杉醇耐药的患者来源的异种移植物 （PDX） 模型，并使用 RNA 测序来识别由 LGALS1 编码的半乳糖凝集素-1 是耐药的关键介质。临床数据和生理学研究的综合分析表明，耐药患者的血清半乳糖凝集素-1 水平升高，并与紫杉烷治疗前后的治疗结果相关。重要的是，与敏感患者的血清相比，将细胞暴露于耐药患者的血清中导致紫杉醇耐药性增加，这与血清中的半乳糖凝集素-1 浓度密切相关。半乳糖凝集素-1 从耐药患者血清中的特异性清除显着恢复了紫杉醇敏感性，并通过敲低或药物抑制剂 OTX008 抑制半乳糖凝集素-1，增加了对紫杉醇的敏感性。半乳糖凝集素-1 抑制降低了 β-catenin 的活性，从而抑制了 Wnt/β-catenin 通路诱导的干细胞特性。此外，半乳糖凝集素-1 通过增加 β-catenin 的核积累来调节 MDR1 转录，从而增加对紫杉醇的耐药性。OTX008 与临床紫杉烷制剂联合使用，在体外和体内有效逆转了紫杉醇耐药性。因此，半乳糖凝集素 1 水平升高可作为 ESCC 对紫杉醇治疗反应的指标，为克服耐药性提供了一种治疗干预策略。