Abstract 894: CXCR1: A novel therapeutic avenue for CSC-like phenotypes in pancreatic ductal adenocarcinoma

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the United States. Often diagnosed late in disease progression, PDAC is notorious for chemotherapy resistance as well as having metastases. A cell population of interest aiding in this progression is the cancer stem cell (CSC). These cells are known for having high resistance to chemotherapy, along with propagating and re-building the tumor after most non-CSCs have been therapeutically targeted. Previous studies have determined CXCR4, ALDH1, CD24, CD44, and CD133 are markers of PDAC CSCs. In the present study, we investigated CXCR1 as a marker and therapeutic target for PDAC CSCs. CXCR1 is a G-coupled transmembrane protein receptor with downstream effects known to aid in anti-apoptosis, proliferation, and angiogenesis via binding CXCL8 and CXCL6. Already known to be a CSC marker and target in triple-negative breast cancer, initial studies by Chen et al. of CXCR1 in PDAC demonstrate CXCL8 induces increased tumorsphere formation in vitro, leading us to investigate CXCR1 in PDAC CSCs. Considering these findings, we hypothesized that PDAC cells with high CXCR1 activity exhibit increased CSC-like characteristics, and targeting CXCR1 will reduce those characteristics. To investigate the role of CXCR1 in PDAC CSC-like phenotype, we used two PDAC cell lines, CD18/HPAF and T3M4, and developed gemcitabine resistant (GemR) counterparts. These GemR cell lines were shown to have over 10-fold higher resistance than their respective parent cell lines. We treated with the CXCR1/2 antagonist navarixin at concentrations known to inhibit CXCR1. Using the parent cell lines’ relative IC50 concentrations for each drug, we treated cells for 72 hours. We used qRT-PCR and ELISAs for analysis of several known CSC markers and CXCR1 axis expression. From our results, we see the beginning trends of GemR cells having increased expression of CSC markers as well as gemcitabine-treated parent and resistant cells having increased expression. Using flow cytometry, we evaluated the CXCR1+ cell populations post-control and gemcitabine treatment. The population of CXCR1+ cells was higher in the gemcitabine-treated groups. Together, our observations suggest an association between CXCR1 and the CSC-like phenotype in PDAC. Citation Format: Caitlin Molczyk, Elizabeth Thomas, Lubaba Zaman, Paran Goel, Rakesh K. Singh. CXCR1: A novel therapeutic avenue for CSC-like phenotypes in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 894.