Targeting WFS1 overcomes KRAS^G12D dependency and adaptive resistance to KRAS inhibition in pancreatic cancer

KRAS^G12D-driven pancreatic ductal adenocarcinoma (PDAC) remains a therapeutic challenge characterized by limited treatment options. While MRTX1133, a potent and selective KRAS^G12D inhibitor, is currently under clinical evaluation, the emergence of acquired resistance restricts its long-term therapeutic efficacy. In this study, we identified Wolfram syndrome 1 (WFS1) as a potential molecular vulnerability in KRAS^G12D-driven PDAC. Our findings suggest that WFS1 expression is upregulated following KRAS^G12D activation and may promote tumorigenesis and metastasis. Moreover, WFS1 expression was further elevated in tumors resistant to MRTX1133, independently of KRAS activation status. Inhibition of WFS1 partially restored sensitivity to MRTX1133 in resistant tumors by inducing excessive and sustained activation of the unfolded protein response (UPR), subsequently triggering apoptosis. Further exploration revealed that, while WFS1 is regulated by the MAPK and PI3K/AKT pathways in MRTX1133-sensitive cells, acquired resistance is associated with downregulation of the E3 ubiquitin ligase Smurf1, leading to increased WFS1 protein stability. Overall, these results highlight WFS1 as an adaptive factor and potential therapeutic target in KRAS^G12D-driven malignancies, offering a novel approach to enhance the efficacy of KRAS^G12D inhibitors and overcome acquired resistance.