Abstract B064: xCT promotes SMAD signaling to induce gemcitabine resistance in KRAS-mutated pancreatic cancer

Abstract

KRAS mutations are highly prevalent in pancreatic ductal adenocarcinoma (PDAC), leading to poor prognosis. Although gemcitabine is mainly utilized as the first-line treatment, patients with PDAC often develop resistance. However, the underlying mechanism of gemcitabine resistance in KRAS-mutant PDAC remains unclear. Therefore, it is necessary to elucidate underlying mechanism that causes drug resistance. In this study, we identified SLC7A11 as the most differentially upregulated gene across KRAS-mutant gemcitabine-resistant (GR) PDAC cells and tumors by comparing KRAS G12D mutant against KRAS wild-type GR cells via transcriptomic analyses. To confirm the functional effects of SLC7A11, we performed cell viability, migration, and invasion assays revealing that SLC7A11 depletion reduced tumorigenic phenotypes. Moreover, lipid ROS and glutathione assays showed enhanced ferroptosis in SLC7A11-deficient chemoresistant KRAS-mutant PDAC cells. To investigate how SLC7A11 induces gemcitabine resistance, we performed gene ontology (GO) analysis and revealed that SMAD and TGF-β signaling pathways were upregulated in KRAS-mutant GR PDAC cells. Furthermore, we found that SLC7A11 enhances SMAD signaling by regulating a deubiquitinating enzyme that inhibits SMAD degradation. In addition, SLC7A11 inhibition led to reduced tumor growth and increased gemcitabine sensitivity in vivo. Altogether, our results demonstrate that SLC7A11 promotes gemcitabine resistance via upregulation of SMAD signaling pathway in KRAS-mutant pancreatic cancer.