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Targeting the IRAK1-S100A9 Axis Overcomes Resistance to Paclitaxel in Nasopharyngeal Carcinoma.
- Source :
-
Cancer research [Cancer Res] 2021 Mar 01; Vol. 81 (5), pp. 1413-1425. Date of Electronic Publication: 2021 Jan 05. - Publication Year :
- 2021
-
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.<br /> (©2021 American Association for Cancer Research.)
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 81
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 33402387
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-20-2125