Exploring the Mechanism of Elraglusib Resistant on Pancreatic Cancer
Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy with a dismal 5-year survival rate, highlighting the urgent need to improve drug response and overcome acquired resistance to conventional chemotherapy. Glycogen synthase kinase 3β (GSK-3β) is a target in PDAC, and significantly, an GSK-3 inhibitor Elraglusib, has been shown to improve the chemosensitivity of PDAC and survival in preclinical cancer models. In addition, results from an ongoing randomized phase II clinical trial in patients with newly diagnosed pancreatic cancer suggests that patients receiving a combination of nab-paclitaxel/gemcitabine and Elraglusib are having lasting durable responses, as compared to those getting only nab-paclitaxel/gemcitabine. While this early evidence is highly encouraging, the biological determinants of elraglusib response are unknown, as are potential mechanisms of resistance. To address this, we developed paired Elraglusib sensitive and resistant cell lines by selecting three pancreatic cancer cell lines in the continued presence of Elraglusib and assessing their sensitivity using the clonogenic assay. Subsequently, we performed RNA-seq on the paired cell lines. Following bioinformatic analysis, we found that of the over 300 commonly increased genes in three resistant cell lines, two family members from the Aldo-Keto Reductase Family 1 (AKR1C), AKR1C1 and AKR1C2 had the highest fold change. The upregulation of AKR1C1 and AKR1C2 mRNA expression in Elraglusib-resistant cell lines were further confirmed by quantitative PCR and have a direct impact on accumulated protein level examined by immunoblotting. Nevertheless, using CRISPR-Cas9 mediated gene editing technique, we have generated AKR1C2 knockout cell line to examine the requirement of AKR1C2 in developing Elraglusib resistance. Together, we have built here a preclinical model to explore the potential mechanisms for Elraglusib resistance, and results from our study could lead to discovery of biomarkers for Elraglusib sensitivity in clinical trials.