AGR2-Dependent Nuclear Import of RNA Polymerase II Constitutes a Specific Target of Pancreatic Ductal Adenocarcinoma in the Context of Wild-Type p53 PMID: 34303658

ADC Targets in Oncology

2026-04-10

AGR2-Dependent Nuclear Import of RNA Polymerase II Constitutes a Specific Target of Pancreatic Ductal Adenocarcinoma in the Context of Wild-Type p53

Gastroenterology. 2021 Nov;161(5):1601-1614.e23. doi: 10.1053/j.gastro.2021.07.030.

Zhiheng Zhang ¹ , Hongzhen Li ² , Yibin Deng ³ , Kathleen Schuck ⁴ , Susanne Raulefs ¹ , Nadja Maeritz ¹ , Yuanyuan Yu ⁴ , Torsten Hechler ⁵ , Andreas Pahl ⁵ , Vanesa Fernández-Sáiz ⁶ , Yuan Wan ⁷ , Guosheng Wang ⁷ , Thomas Engleitner ⁸ , Rupert Öllinger ⁹ , Roland Rad ⁹ , Maximilian Reichert ¹⁰ , Kalliope N Diakopoulos ¹¹ , Verena Weber ¹ , Jingjing Li ¹² , Shanshan Shen ¹² , Xiaoping Zou ¹² , Jörg Kleeff ¹³ , Andre Mihaljevic ⁴ , Christoph W Michalski ⁴ , Hana Algül ¹¹ , Helmut Friess ¹ , Bo Kong ¹⁴

Affiliations

1. Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
2. Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, China; Department of Surgery, Ulm University Hospital, Ulm University, Ulm, Germany.
3. Jiangsu Key Laboratory of Neuropsychiatric Diseases, and College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
4. Department of Surgery, Ulm University Hospital, Ulm University, Ulm, Germany.
5. Heidelberg Pharma Research GmbH, Ladenburg, Germany.
6. Department of Medicine III, Klinikum rechts der Isar, Technische Universität München, Munich, Germany; Center for Translational Cancer Research, Technische Universität München, Munich, Germany.
7. The Pq Laboratory of Micro/Nano BiomeDx, Department of Biomedical Engineering, Binghamton University, State University of New York, Binghamton, New York.
8. Center for Translational Cancer Research, Technische Universität München, Munich, Germany; Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany; Comprehensive Cancer Center Munich, Technical University of Munich, Munich, Germany.
9. Center for Translational Cancer Research, Technische Universität München, Munich, Germany; Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany; German Cancer Consortium at the partner site Munich, Munich, Germany.
10. Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
11. Comprehensive Cancer Center Munich, Technical University of Munich, Munich, Germany.
12. Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, China.
13. Department of Visceral, Vascular and Endocrine Surgery, Martin Luther University Halle-Wittenberg, Halle, Germany.
14. Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, China; Department of Surgery, Ulm University Hospital, Ulm University, Ulm, Germany. Electronic address: [email protected].

Abstract

Background & aims: Promoted by pancreatitis, oncogenic Kras^G12D triggers acinar cells' neoplastic transformation through acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia. Anterior gradient 2 (Agr2), a known inhibitor of p53, is detected at early stage of pancreatic ductal adenocarcinoma (PDAC) development. RNA polymerase II (RNAPII) is a key nuclear enzyme; regulation of its nuclear localization in mammalian cells represents a potential therapeutic target.

Methods: A mouse model of inflammation-accelerated Kras^G12D-driven ADM and pancreatic intraepithelial neoplasia development was used. Pancreas-specific Agr2 ablation was performed to access its role in pancreatic carcinogenesis. Hydrophobic hexapeptides loaded in liposomes were developed to disrupt Agr2-RNAPII complex.

Results: We found that Agr2 is up-regulated in ADM-to-pancreatic intraepithelial neoplasia transition in inflammation and Kras^G12D-driven early pancreatic carcinogenesis. Genetic ablation of Agr2 specifically blocks this metaplastic-to-neoplastic process. Mechanistically, Agr2 directs the nuclear import of RNAPII via its C-terminal nuclear localization signal, undermining the ATR-dependent p53 activation in ADM lesions. Because Agr2 binds to the largest subunit of RNAPII in a peptide motif-dependent manner, we developed a hexapeptide to interfere with the nuclear import of RNAPII by competitively disrupting the Agr2-RNAPII complex. This novel hexapeptide leads to dysfunction of RNAPII with concomitant activation of DNA damage response in early neoplastic lesions; hence, it dramatically compromises PDAC initiation in vivo. Moreover, the hexapeptide sensitizes PDAC cells and patient-derived organoids harboring wild-type p53 to RNAPII inhibitors and first-line chemotherapeutic agents in vivo. Of note, this therapeutic effect is efficient across various Cancer types.

Conclusions: Agr2 is identified as a novel adaptor protein for nuclear import of RNAPII in mammalian cells. Also, we provide genetic evidence defining Agr2-dependent nuclear import of RNAPII as a pharmaceutically accessible target for prevention and treatment in PDAC in the context of wild-type p53.

Keywords

Agr2; Hexapeptide; Metaplastic; Neoplastic; Pancreatic Cancer.