Abstract B026: Sustained KRAS-MAPK Inhibition Induces Interferon-mediated Epithelial-to-Mesenchymal Transition and Reveals a Potential Therapeutic Opportunity

Abstract

: Therapeutic targeting of the KRAS-MAPK pathway has been clinically unsuccessful in pancreatic ductal adenocarcinoma (PDAC) until recently, with the advent of KRAS inhibitors that have shown promising efficacy in clinical trials. However, treatment resistance remains a challenge. Analysis of human PDAC samples and patient-derived cell lines treated with the ERK inhibitor ulixertinib revealed prominent upregulation of interferon and epithelial-to-mesenchymal transition (EMT) signatures. We identify TRIM22, an interferon-inducible E3 ubiquitin ligase upregulated following KRAS and MAPK inhibition, as a key mediator that drives EMT, at least in part by promoting the degradation of IκBα and thus activating NF-κB signaling. We further show that TACSTD2, which encodes TROP2, is an NF-κB target gene that is upregulated following EMT. On this basis, combining ulixertinib or the KRAS^G12D inhibitor MRTX1133 with the TROP2-directed antibody-drug conjugate sacituzumab govitecan markedly suppresses the growth of PDAC patient-derived xenografts (PDXs). Together, our study uncovers TRIM22 as a molecular link between interferon signaling and EMT and nominates TROP2 as a druggable vulnerability that can be co-targeted to augment the therapeutic efficacy of KRAS-MAPK pathway inhibitors. Citation Format: Ashenfi S. Bulle, Timothy Hung-Po Chen, Iftikhar Khawar, Huaping Li, Vikas Somani, Lim Kian-Huat, Ashenfi S. Bulle. Sustained KRAS-MAPK Inhibition Induces Interferon-mediated Epithelial-to-Mesenchymal Transition and Reveals a Potential Therapeutic Opportunity [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): nr B026.