Abstract 3121: Characterization of nab-paclitaxel resistant and gemcitabine resistant BxPC3 and MIA PaCa-2 pancreatic cancer cells

Abstract

Abstract The gemcitabine (Gem) and nab-paclitaxel (Nab-p) combination is currently the FDA approved standard of care for patients with Stage IV metastatic pancreatic cancer. The response rate of the Gem and Nab-p regimen ranges from 23% to 46%, with many patients eventually becoming refractory. The specific aim of this research project is to determine which genes and pathways differ in Gem resistant (GemR) or Nab-p resistant (Nab-pR) MIA PaCa2 (MP2) and BxPC3 cells when compared with their parental cell lines. Cell proliferation assays were carried out to confirm resistance of the cell lines. The IC50 values of gemcitabine in the Gem resistant BxPC3 (BxPC3-GemR) and MP2 (MP2-GemR) are 26 and 64 fold higher than those in the corresponding parental cell lines, respectively. The IC50 values of nab-paclitaxel in the Nab-p resistant BxPC3 (BxPC3-Nab-pR) and MP2 (MP2-Nab-pR) are 13 and 140 fold higher than those in the corresponding parental cell lines, respectively. RNA sequencing (RNA-seq) was then performed to compare the gene expression profiles of the parental and resistant cell lines. Gene set enrichment analysis (GSEA) revealed that differentially expressed genes between Gem resistant and parental BxPC3 cell lines are often enriched in pathways associated with endoplasmic reticulum (ER) stress response (e.g. ATF-6 and XBP1) whereas in MP2 cells, The AMPK signaling pathway (e.g. PRKAB1, and PRKAG1) seemed to be activated in Gem resistant cells. NFkB signaling pathway (e.g. RIPK2 and NFKB2) was elevated in both Nab-p resistant BxPC3 and MP2 cell lines compared to their corresponding parental cell lines. Genes from these pathways were selected for further validation of their differential expression using RT-PCR. ATF6 which is a stress sensor and transducer in the ER is upregulated in BxPC3-GemR. PRKAB1 and PRKAG1 which regulate AMPK activity are upregulated in MP2-GemR. RIPK2 and NFKB1 are both up in the Nab-p resistant cell lines. Results from this study could provide insights on how to devise new therapeutic regimens to overcome resistance to gemcitabine and nab-paclitaxel. Citation Format: Danielle M. Arias, John Collins, Pawan Noel, Daniel D. Von Hoff, Haiyong Han. Characterization of nab-paclitaxel resistant and gemcitabine resistant BxPC3 and MIA PaCa-2 pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3121.