PO-248 The role of ER stress in arginine deprivation-induced radiosensitization and cell death of HNSCC cells

Abstract

IntroductionPancreatic ductal adenocarcinoma (pdac) is one of the most lethal human cancers. about 20–30% of pdac are described to be auxotrophic for arginine and thus might be particularly sensitive to arginine deprivation therapy (adt). although radiotherapy for treatment of pdca is controversially discussed, the abnormal metabolism of pdac in combination with radiation is an attractive approach for targeted therapy. previously, we could show that adt is efficient in radiosensitizing auxotrophic pdacs to photons. recent clinical studies imply a benefit of proton radiotherapy for pdac patients. we therefore systematically compared the sensitivity of pdac cells to photon and proton irradiation in combination with adt as well as gemcitabine treatment.Material and methodsHuman and murine auxotrophic pdacs cells mimicking a patient cohort were studied. adt was achieved with 2 u/ml of recombinant human arginase +/- citrulline, a physiological precursor of arginine. single doses ≤ 30 gy of 200 kv x-rays or 150 mev double-scattered protons were applied. treatment response was assessed by 2-d clonogenic survival and/or 3-d spheroid control probability (scp) assays.results and discussionsadt led to a sensitization of pdac cells to x-rays in 2-d and 3-d culture. proton irradiation significantly reduced the scp and spheroid control dose 50% (scd50) relative to x-rays in the 3-d assay as reflected by a relative biological effectiveness (rbe) of 2.0. combining protons with adt further increased the rbe to 2.4. gemcitabine treatment did not improve radiotherapy outcome. however, the triple combination of adt, gemcitabine and proton irradiation had a highly synergistic effect (rbe = 3.0). extended mechanistic studies are ongoing.ConclusionFor pdac, adt in combination with gemcitabine and proton irradiation seems to be a very promising treatment strategy and should be further explored for translation into clinical trials.