What question did this study set out to answer?

This research aims to understand how prolonged KRAS-MAPK inhibition affects signaling pathways and tumor resistance mechanisms in pancreatic cancer.

April 5, 2026

Abstract 1874: Prolonged KRAS-MAPK inhibition activates interferon signaling to promote cellular plasticity and uncover novel targets for combination therapy.

Key Points

This research aims to understand how prolonged KRAS-MAPK inhibition affects signaling pathways and tumor resistance mechanisms in pancreatic cancer.
Analyzed PDAC specimens and cells treated with ERK inhibitors.
Examined effects of prolonged KRAS inhibition on signaling pathways.
Utilized the GeneRep-nSCORE framework to identify key mediators of EMT and resistance.
Evaluated the effects of combining ulixertinib or MRTX1133 with sacituzumab govitecan on patient-derived xenografts.
ERK inhibition led to upregulation of EMT and interferon signaling in PDAC cells.
TRIM22 was identified as a key mediator of EMT by promoting proteasomal degradation of IκBα and activating NF-κB.
TROP2 was found to be an NF-κB target gene upregulated after EMT.
Combination therapies effectively suppressed the growth of PDAC patient-derived xenografts.

Abstract

Abstract KRAS-MAPK cascade inhibition shows promise for treating PDAC. However, resistance arises through secondary mutations that restore MAPK signaling and trigger epithelial-to-mesenchymal transition (EMT), key mechanisms of acquired resistance. Here, we show that human PDAC specimens and cells treated long-term with an ERK inhibitor exhibit upregulation of EMT and interferon signaling, with similar pattern also seen following prolonged KRAS inhibition in PDAC cells. Using the GeneRep-nSCORE framework, we identified TRIM22, an interferon-inducible E3 ubiquitin ligase, as a key mediator of EMT and resistance by promoting proteasomal degradation of IκBα and activating NF-κB signaling. Searching for druggable targets, we found TACSTD2 (TROP2), an NF-κB target gene upregulated after EMT. Combining ulixertinib or the KRAS inhibitor MRTX1133 with the TROP2-directed antibody-drug conjugate sacituzumab govitecan effectively suppressed growth of PDAC patient-derived xenografts. This study highlights TRIM22’s role in linking interferon signaling with EMT and identifies TROP2 as a therapeutic vulnerability to overcome acquired resistance. Citation Format: Ashenafi Shiferaw Bulle, Yali Chen, Huaping Li, Hung-Po Chen, Iftikhar Ali Khawar, Lin Li, Yu Wang, Peng Liu, Vikas Kumar Somani, Richard Kurupi, Sapana Prakashrao Bansod, Son Bang Le, Marianna Ruzinova, David D Tran, Kian-Huat Lim. Prolonged KRAS-MAPK inhibition activates interferon signaling to promote cellular plasticity and uncover novel targets for combination therapy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1874.

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