Abstract Background: The prognosis of recurrent and metastatic Ewing sarcoma (EWS) is extremely poor and the problem of drug resistance is significant; thus, it is extremely important to identify the mechanisms underlying chemotherapy resistance. This study aimed to explore the genes associated with chemotherapy resistance in EWS. Procedure: Gene expression profile data of GSE12102 and GSE63155were downloaded from GEO to screen for differentially expressed genes (DEGs). GO functional annotation analysis was performed on common DEGs. Twenty-one patients were divided into good response (tumor necrosis rate ≥90%) (n=4) and poor response (tumor necrosis rate <90%) (n=17) groups to chemotherapy. Formalin-fixed paraffin-embedded (FFPE) tissues of 21 patients after chemotherapy and 5 patients who are in poor response group before chemotherapy were collected. Real-Time Quantitative Reverse Transcription PCR(qRT-PCR) was used to verify gene expression differences.. The relationship between prognosis and gene expression level verified by GSE17679 Results: The PGAP6 expression level after chemotherapy in the poor response group (2.78 ± 2.36) was higher than that in the good response group (1.16 ± 0.65) (P = 0.024). Expression of PGAP6 after chemotherapy (16.70 ± 13.78) was higher than that before chemotherapy (1.16 ± 0.62; P = 0.071). Verified by external datasets, the expression level of PGAP6 was related to prognosis. Conclusions: PGAP6 drives EWS chemoresistance and may be associated with acquired resistance. The expression levels of PGAP6 correlated with EWS prognosis. PGAP6 can be used as a new target for reversing chemotherapy resistance of EWS. KEYWORDS: Ewing sarcoma; chemotherapy; drug resistance; PGAP6; TMEM8A

Survival of patients with recurrent and metastatic Ewing sarcoma (ES) has not markedly improved in the last 40 years; the main reason for the poor prognosis of these patients is drug resistance. However, intrinsic and acquired resistance may occur in response to both traditional chemotherapy and targeted drugs. These complex mechanisms plausibly include instability of the genetic material, enhanced drug efflux and metabolism, positive DNA repair, inhibition of tumor cell apoptosis, miRNAs, the tumor microenvironment, cancer stem cells, autophagy, and the activation of cell proliferation pathways. The development and application of nanoparticles bring new hope for reversing drug resistance in ES, accompanied with encouraging results from preclinical trials. In this review, we elucidate the molecular mechanisms underlying drug resistance in ES and propose putative strategies to overcome this resistance to improve prognosis of patients with ES.