Abstract B036: Uncovering the dual roles of XBP1 in pancreatic ductal adenocarcinoma during lipid imbalance and KRAS inhibitor resistance

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by dense desmoplasia, which leads to impaired intratumoral perfusion and elevated interstitial fluid pressure. These conditions create regions of severe oxygen and nutrient deprivation. One consequence is a deficiency in unsaturated fatty acids (uFAs), as their de novo synthesis is oxygen-dependent. We found that uFA deprivation induces endoplasmic reticulum (ER) stress in PDAC cells, activating canonical ER stress responses, particularly the inositol-requiring enzyme 1α (IRE1α) - X-box binding protein 1 (XBP1) signaling axis. IRE1α-mediated splicing of XBP1 mRNA generates XBP1s, a transcription factor that modulates lipid metabolism. XBP1s expression is elevated in PDAC compared to PanIN and normal tissues in both mouse models and human samples. Interestingly, human PDAC samples exhibit focal XBP1s expression patterns, which may correlate with stromal distribution and local uFA availability. In vitro, XBP1 knockdown significantly improves PDAC cell viability under lipid-depleted, low-oxygen conditions across multiple human and mouse cell lines. Similarly, pharmacological inhibition of IRE1α RNase activity using B-I09 rescues cell viability under lipid imbalance. However, neither XBP1 knockdown nor B-I09 treatment enhances tumor growth or viability in vivo. To mimic in vivo uFA depletion, we implemented a calorie restriction (CR) diet in mice, but XBP1 knockdown again failed to confer a survival benefit, possibly due to compensatory uFA supply from tumor-associated fibroblasts. Despite its cytotoxic role under lipid-deprived conditions, we discovered a contrasting function of XBP1 in mediating the survival of PDAC cells resistant to the KRASG12D inhibitor MRTX1133 (KRASi). In KRASi-resistant cells, XBP1 knockdown or B-I09 treatment significantly impairs cell viability, more so than in parental cells. Notably, supplementation with oleic acid, a monounsaturated fatty acid, rescues B-I09-induced cell death in resistant cells, suggesting that lipid metabolism contributes to KRASi resistance. Together, these findings highlight a context-dependent, dual role of XBP1 in PDAC: promoting cell death under lipid imbalance while supporting the survival of KRASi-resistant cells. Ongoing work aims to determine the therapeutic potential of targeting XBP1 in KRASi-resistant PDAC and to identify the specific lipid species involved in mediating resistance. Additionally, although B-I09 rescues cell viability under lipid imbalance across both classical and basal PDAC subtypes, we are currently investigating whether these subtypes exhibit differential sensitivity to the combination of KRAS inhibition and B-I09. Citation Format: Yanqing (Christine) Jiang, Carson Poltorack, Rowena Yin, Morgan Brown, Yizheng Xue, John Tobias, Yihui Shen, Brian Keith, M. Celeste Simon. Uncovering the dual roles of XBP1 in pancreatic ductal adenocarcinoma during lipid imbalance and KRAS inhibitor resistance [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B036.