%0 Journal Article
%T Identification of the unfolded protein response pathway as target for radiosensitization in pancreatic cancer.
%A Kern J
%A Schilling D
%A Schneeweis C
%A Schmid RM
%A Schneider G
%A Combs SE
%A Dobiasch S
%J Radiother Oncol
%V 191
%N 0
%D 2024 Feb 20
%M 38135186
%F 6.901
%R 10.1016/j.radonc.2023.110059
%X <B>OBJECTIVE: </B>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.<BR><B>METHODS: </B>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.<BR><B>RESULTS: </B>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.<BR><B>CONCLUSIONS: </B>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.