1. Targeting the IRAK1-S100A9 Axis Overcomes Resistance to Paclitaxel in Nasopharyngeal Carcinoma.
- Author
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Liu L, Liu S, Deng P, Liang Y, Xiao R, Tang LQ, Chen J, Chen QY, Guan P, Yan SM, Huang X, Hong JH, Chen J, Sun Y, Teh BT, Yu Q, Mai HQ, and Tan J
- Subjects
- Animals, Antineoplastic Agents, Phytogenic pharmacology, Bridged-Ring Compounds pharmacology, Calgranulin B genetics, Cell Line, Tumor, 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, Inbred BALB C, Molecular Targeted Therapy, Nasopharyngeal Carcinoma genetics, Nasopharyngeal Carcinoma mortality, Nasopharyngeal Neoplasms genetics, Nasopharyngeal Neoplasms mortality, Prognosis, Pyrimidines pharmacology, Xenograft Model Antitumor Assays, Mice, Calgranulin B metabolism, Drug Resistance, Neoplasm drug effects, Nasopharyngeal Carcinoma drug therapy, Nasopharyngeal Neoplasms drug therapy, Paclitaxel pharmacology
- Abstract
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., (©2021 American Association for Cancer Research.)
- Published
- 2021
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