Abstract 5876: ALDH3A1 as a predictive marker for gemcitabine treatment in pancreatic cancer

Abstract

Abstract Background: Pancreatic cancer is one of the incurable cancer. The currently preferred chemotherapy regimens, including gemcitabine, do not extend patient survival by more than a year, and studies on drug resistance mechanisms or biomarkers for the drug sensitivity are very limited. Aldehyde dehydrogenase (ALDH) is a family of enzymes that play an essential role in cell survival and protection. In cancer cells, it is thought that overexpression of the ALDHs confers a survival advantage to the cells, which is associated with a poor prognosis. In this study, we analyzed the drug sensitivity between ALDH3A1 expression and gemcitabine in PDAC cells. Method: In this study, we investigated the relationship between ALDH3A1 expression and gemcitabine sensitivity using 8 pancreatic cancer cell line. We observed changes in the pattern of ALDH3A1 expression in established gemcitabine resistance pancreatic cancer cell line. Following this, we functionally inhibited ALDH3A1 to determine its impact on gemcitabine sensitivity using shRNA method. To elucidate the molecular mechanisms related with ALDH3A1, we performed multi-omics analysis such as transcriptomics and proteomics. Results: As a results, there was a negative correlation between ALDH3A1 expression (Protein & mRNA) and gemcitabine resistance 8 pancreatic cancer cell lines. However, in established gemcitabine resistance BxPC3 cells compared to control cells, gemcitabine resistance increased more than 1000 fold while the protein expression was decreased. In these results correlated with inhibition of ALDH3A1 expression using shALDH3A1 experiments both change ALDH3A1 expression and gemcitabine resistance. In biological phenotype experiments, cell proliferation and migration increased in the ALDH3A1 inhibition groups. When using combination treatment of gemcitabine and CB29, a known ALDH3A1 inhibitor, drug resistance increased by more than 2,000 fold in the combination treatment groups. In RNAseq analysis, Adherens junction, Ras signaling, Axon guidance, and JAK-STAT signaling pathway related genes were up regulated in shALDH3A1 treatment group compared control. Conclusion: In this study, we demonstrated the negative correlation between ALDH3A1 and gemcitabine resistant in pancreatic cancer cell lines and suggesting that it may serves as a predictive marker for gemcitabine treatment in pancreatic cancer patients. Keywords: Pancreatic ductal adenocarcinoma (PDAC), Aldehyde dehydrogenase 3 family member A1 (ALDH3A1), Gemcitabine sensitivity. Citation Format: Jin Su Kim, Ji Young Keum, Chan Hee Park, Seungmin Bang. ALDH3A1 as a predictive marker for gemcitabine treatment in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5876.