Targeting the IRAK1-S100A9 Axis Overcomes Resistance to Paclitaxel in Nasopharyngeal Carcinoma

• Published in: Cancer research (Chicago, Ill.) Ill.), 2021-03, Vol.81 (5), p.1413-1425
• Main Authors: Liu, Lizhen, Liu, Sailan, Deng, Peng, Liang, Yujing, Xiao, Rong, Tang, Lin-Quan, Chen, Jinghong, Chen, Qiu-Yan, Guan, Peiyong, Yan, Shu-Mei, Huang, Xiangliang, Hong, Jing Han, Chen, Jianfeng, Sun, Yichen, Teh, Bin Tean, Yu, Qiang, Mai, Hai-Qiang, Tan, Jing
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents, Phytogenic - pharmacology; Bridged-Ring Compounds - pharmacology; Calgranulin B - genetics; Calgranulin B - metabolism; Cell Line, Tumor; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - physiology; Drug Screening Assays, Antitumor; Female; Humans; Interleukin-1 Receptor-Associated Kinases - antagonists & inhibitors; Interleukin-1 Receptor-Associated Kinases - genetics; Interleukin-1 Receptor-Associated Kinases - metabolism; Mice; Mice, Inbred BALB C; Molecular Targeted Therapy; Nasopharyngeal Carcinoma - drug therapy; Nasopharyngeal Carcinoma - genetics; Nasopharyngeal Carcinoma - mortality; Nasopharyngeal Neoplasms - drug therapy; Nasopharyngeal Neoplasms - genetics; Nasopharyngeal Neoplasms - mortality; Paclitaxel - pharmacology; Prognosis; Pyrimidines - pharmacology; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-20-2125

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 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 expression. Functional studies in both and 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.