Abstract A133: Role of CXCR2 in the acquisition of pan-resistant phenotype in high grade serous ovarian cancer cells

Abstract

Abstract Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy. Indeed, EOC epidemiological scenario is partially due to its late diagnosis, when most of tumor cells have acquired metastatic and chemoresistant phenotype. Despite the initial satisfactory response of EOC cells to platinum/taxanes-based therapy, chemoresistance emerges in an uncontrolled pace, specifically when the patient carries a high-grade serous adenocarcinoma (HGS-AC). Therefore, EOC clinic urges for novel treatment possibilities, aiming the reversal of chemoresistance, the improvement of patients’ quality of life, and their survival rates. cDNA microarray data from our group demonstrated that chemokines secreted to the tumor microenvironment, as CXCL2, IL-6, and IL-8 likely play a crucial role in EOC cells chemoresistance. Thereafter, the present study focused on the role of CXCL2, which binds to its receptor CXCR2 in the membrane of target cells. Nonetheless its function in HGS-AC is unclear. Our study model was based in two HGS-AC lineages: chemosensitive A2780, and its pan-resistant derived ACRP (IC50 to cisplatin 7.3uM vs. 26,56uM, p<0.001; to doxuribicin 0.07uM vs. 1.5uM, p<0.0001, and to paclitaxel 0.22uM vs. 1.7uM, p<0.0001, respectively). CXCR2 was knockdown (KD), and its expression was decreased to 0.6-fold as compared to control cells (p= 0.0015). As compared to the control experimental condition (100%), CXCR2 KD HGS-AC cells described compromised cellular proliferation and metabolic viability (BrdU and Presto blue/SRB assays: A2780 21% vs. ACRP 23%, p<0.0001), and lower cell viability (clonogenic assay: A2780 70% vs. ACRP 49%, p<0.0001). Although angiogenesis does not seem to influence our observations, chicken embryo chorioallantoic membrane assay revealed that CXCR2 KD ACRP-induced tumors shrunk by 3.3-fold in comparison the control condition. Intriguingly, similar results were not observed when cells were treated with the pharmacological inhibitor of CXCR2. We lately discovered that the receptor was anomalously expressed in the cells nucleus, thus justifying our observations while opening novel avenues for future investigations in the field. We, then, argued whether CXCR2 KD would modulate carcinogenic classic signaling pathways. We observed a biological tendency of less P-AKT (0.5- fold, p=0.09), but not P-ERK (0.3-fold, p=0.7) when compared to control. We also investigated the involvement of EMT in our studied phenomena. Our findings demonstrated significative decline in the expression of SLUG (0.9-fold vs. control, p=0.022) and SNAIL (1.1-fold vs. control, p=0.005) in CXCR2 KD ACRP cells. Finally, in silico analysis including over 200 HGS-AC cases revealed that overexpression of CXCR2 is robustly correlated to the worse disease prognosis and patients’ overall survival rate, specially in late stage disease (p=0.035). Altogether, our results present innovative strategy to fight pan-chemoresistant HGS-AC by silencing anomalously overexpressed CXCR2. Citation Format: Taciane Henriques, Diandra dos Santos, Isabella Guimaraes, Nayara Tessarollo, Paulo Lyra, Patricia Mesquisa, Diana Padua, Ana Luisa Amaral, Luisa Pereira, Bruno Cavadas, Ian Silva, Raquel Almeida, Leticia Rangel. Role of CXCR2 in the acquisition of pan-resistant phenotype in high grade serous ovarian cancer cells [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A133. doi:10.1158/1535-7163.TARG-19-A133