Targeting the IRAK1-S100A9 Axis Overcomes Resistance to Paclitaxel in Nasopharyngeal Carcinoma
Targeting the IRAK1-S100A9 Axis Overcomes Resistance to Paclitaxel in Nasopharyngeal Carcinoma
复制标题
靶向 IRAK1-S100A9 轴克服了鼻咽癌对紫杉醇的耐药性。
DOI：
10.1158/0008-5472.can-20-2125
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发表时间：
2021-03-01
期刊：
影响因子：
11.2
通讯作者：
Tan, Jing
中科院分区：
文献类型：
--
作者：
Liu, Lizhen;Liu, Sailan;Tan, Jing
治疗晚期鼻咽癌的新策略往往对化疗产生耐药性，这仍然是一个未得到满足的临床需求。在这项研究中，我们确定了多激酶抑制剂pacritinib能够在获得性耐药模型中对紫杉醇的反应重新敏感。对紫杉醇敏感和耐药细胞系以及化学难治性临床样本的转录组分析，将S100 A9确定为被pacritinib抑制的最佳候选基因，其过表达与紫杉醇耐药和不良临床结局显著相关。此外，紫杉醇耐药的鼻咽癌细胞和复发/转移的临床样品都表现出IRAK 1磷酸化增加，并证明pacritinib可以消除IRAK 1磷酸化以抑制S100 A9表达。体外和体内模型的功能研究表明，IRAK 1的遗传或药物阻断克服了紫杉醇的耐药性，pacritinib与紫杉醇联合治疗显示出上级抗肿瘤作用。总之，这些发现证明了IRAK 1-S100 A9轴在介导紫杉醇耐药性中的重要作用。意义：IRAK 1-S100 A9轴的失调与鼻咽癌的预后不良相关，是鼻咽癌耐药的重要因素，pacritinib可以靶向IRAK 1克服鼻咽癌耐药。
Novel strategies to treat late-stage nasopharyngeal carcinoma that often develop resistance to chemotherapy remains an unmet clinical demand. In this study, we identify the multi-kinase inhibitor pacritinib as capable of resensitizing the response to paclitaxel in an acquired resistance model. Transcriptome analysis of paclitaxel-sensitive and -resistant cell lines, as well as chemorefractory clinical samples, identified S100A9 as the top candidate gene suppressed by pacritinib and whose overexpression was significantly associated with paclitaxel resistance and poor clinical outcome. Moreover, both paclitaxel-resistant nasopharyngeal carcinoma cells and relapsed/metastatic clinical samples exhibited increased IRAK1 phosphorylation and demonstrated that pacritinib could abolish the IRAK1 phosphorylation to suppress S100A9 expression. Functional studies in both in vitro and in vivo models showed that genetic or pharmacologic blockade of IRAK1 overcame the resistance to paclitaxel, and combined treatment of pacritinib with paclitaxel exhibited superior antitumor effect. Together, these findings demonstrate an important role for the IRAK1-S100A9 axis in mediating resistance to paclitaxel. Furthermore, targeting of IRAK1 by pacritinib may provide a novel therapeutic strategy to overcome chemoresistance in nasopharyngeal carcinoma.Significance: Deregulation of the IRAK1-S100A9 axis correlates with poor prognosis, contributes to chemoresistance in nasopharyngeal carcinoma, and can be targeted by pacritinib to overcome chemoresistance in nasopharyngeal carcinoma.