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

Resistance to chemotherapy is one of the main causes of mortality in late-stage nasopharyngeal carcinoma (NPC) with dismal prognosis and limited therapeutic options. Therefore, there is an urgent need to exploit new therapeutic targets to improve current clinical outcome. In this study, we identified pacritinib, a late stage clinical drug targeting IRAK1, as a sensitizer to resistance of paclitaxel in NPC. Through analysis of both chemoresistant cellular models and clinical samples of relapse and metastasis, we have shown that aberrant IRAK1-S100A9 deregulation is correlated with chemoresistance and prognosticates poor clinical outcome. Further functional studies demonstrated that genetic and pharmacological inhibition of IRAK1-S100A9 axis overcomes the resistance to paclitaxel and combination of pacritinib with paclitaxel exhibited superior anti-tumor effect in both in vivo and in vitro models. Overall design: 1.RNA-seq for S26 patental (S26 P) cells, S26 resistant cells (S26 R) and S26 R cells treated with pacritinib (Pac) (duplicate). 2.RNA-seq for 22 human tissue samples including 8 NPC samples with complete response (CR) and 14 samples with partially response (PR) to paclitaxel-based chemotherapy.