2. Academic Validation
  3. Identification of the unfolded protein response pathway as target for radiosensitization in pancreatic cancer

Identification of the unfolded protein response pathway as target for radiosensitization in pancreatic cancer

  • Radiother Oncol. 2023 Dec 20:110059. doi: 10.1016/j.radonc.2023.110059.
Jana Kern 1,  Daniela Schilling 2,  Christian Schneeweis 3,  Roland M Schmid 3,  Günter Schneider 4,  Stephanie E Combs 5,  Sophie Dobiasch 6
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, School of Medicine, Klinikum rechts der Isar, Technical University Munich (TUM), Munich, Germany.
  • 2 Department of Radiation Oncology, School of Medicine, Klinikum rechts der Isar, Technical University Munich (TUM), Munich, Germany; Institute of Radiation Medicine (IRM), Department of Radiation Sciences, Helmholtz Zentrum Munich, Neuherberg, Germany.
  • 3 Department of Medicine II, School of Medicine, Klinikum rechts der Isar, Technical University Munich (TUM), Munich, Germany.
  • 4 Department of Medicine II, School of Medicine, Klinikum rechts der Isar, Technical University Munich (TUM), Munich, Germany; Department of General Visceral and Pediatric Surgery, University Medical Center Göttingen, Germany.
  • 5 Department of Radiation Oncology, School of Medicine, Klinikum rechts der Isar, Technical University Munich (TUM), Munich, Germany; Institute of Radiation Medicine (IRM), Department of Radiation Sciences, Helmholtz Zentrum Munich, Neuherberg, Germany; German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany.
  • 6 Department of Radiation Oncology, School of Medicine, Klinikum rechts der Isar, Technical University Munich (TUM), Munich, Germany; Institute of Radiation Medicine (IRM), Department of Radiation Sciences, Helmholtz Zentrum Munich, Neuherberg, Germany; German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany. Electronic address: sophie.dobiasch@tum.de.
PMID: 38135186 DOI: 10.1016/j.radonc.2023.110059
Abstract

Background and purpose: Due to the high intrinsic radioresistance of pancreatic ductal adenocarcinoma (PDAC), radiotherapy (RT) is only beneficial in 30% of patients. Therefore, this study aimed to identify targets to improve the efficacy of RT in PDAC.

Materials and methods: Alamar Blue proliferation and colony formation assay (CFA) were used to determine the radioresponse of a cohort of 38 murine PDAC cell lines. A gene set enrichment analysis was performed to reveal differentially expressed pathways. CFA, cell cycle distribution, γH2AX FACS analysis, and Caspase 3/7 SYTOX assay were used to examine the effect of a combination treatment using KIRA8 as an IRE1α-inhibitor and Ceapin-A7 as an inhibitor against ATF6.

Results: The unfolded protein response (UPR) was identified as a pathway highly expressed in radioresistant cell lines. Using the IRE1α-inhibitor KIRA8 or the ATF6-inhibitor Ceapin-A7 in combination with radiation, a radiosensitizing effect was observed in radioresistant cell lines, but no substantial alteration of the radioresponse in radiosensitive cell lines. Mechanistically, increased Apoptosis by KIRA8 in combination with radiation and a cell cycle arrest in the G1 phase after ATF6 inhibition and radiation have been observed in radioresistant cell lines.

Conclusion: So, our data show evidence that the UPR is involved in radioresistance of PDAC. Increased Apoptosis and a G1 cell cycle arrest seem to be responsible for the radiosensitizing effect of UPR inhibition. These findings are supportive for developing novel combination treatment concepts in PDAC to overcome radioresistance.

Keywords

ATF6; IRE1α; pancreatic ductal adenocarcinoma; radiosensitization; radiotherapy; unfolded protein response.

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