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UBE2N AS A PROMISING NEW RESPONSE MARKER TO CHEMOTHERAPY IN PANCREATIC DUCTAL ADENOCARCINOMA – RESULTS FROM MASS SPECTROMETRY ANALYSES OF NEOADJUVANT TREATED PANCREATIC CANCER
Lennart von Fritsch^*1, Jannis Duhn¹, Maren Drenckhan¹, Lorena Llontop¹, Cristina Ferrone², Vikram Deshpande³, Oliver Schilling⁴, Jutta Kirfel⁵, Rüdiger Braun¹, Louisa Bolm¹, Ulrich F. Wellner¹, Tobias Keck¹, Kim C. Honselmann^1
1University Medical Center Schleswig-Holstein Department of Surgery, Luebeck, Germany; ²Cedars-Sinai Medical Center, Los Angeles, CA; ³Beth Israel Deaconess Medical Center Department of Pathology, Boston, MA; ⁴University of Freiburg Department of Pathology, Freiburg, Germany; ⁵University Medical Center Schleswig-Holstein Institute of Pathology, Luebeck, Germany

Introduction
Despite many advances in the diagnostic and treatment of pancreatic ductal adenocarcinoma (PDAC), it still ranks among the most lethal types of carcinomas. Often diagnosed at an inoperable stage, patients can only be offered chemotherapy to slow down the tumor progression, yet the response rates of 10-30% remain poor. Response markers and novel therapeutic targets are desperately needed to improve overall survival.
Methods
Tumor samples at surgery of 41 patients with and without neoadjuvant chemotherapy (FOLFIRINOX) were collected, together with patient data and clinical data on disease recurrence and death. After preprocessing, label-free quantification mass spectrometry was performed. For further analyses, neoadjuvant treated patients were grouped into short-term survivors (<24 months, sts) and long-term survivors (> 24 months, lts). Naïve patients were used as control. Differences in the resulting proteomes were assessed using R. Furthermore, immunohistochemistry (IHC) staining for UBE2N, and hematoxylin and eosin (H&E) staining each were performed on PDAC tissue of another 40 neoadjuvant treated patients. Tumor tissue was identified by an experienced pathologist on H&E slides. H-scores of the tumor tissue on digitized IHC slides were calculated using QuPath Version 0.5.0 and compared using a Mann-Whitney-U test for sts vs. lts-group.
Results
Of all neoadjuvant treated patients (n=29), 15 fell in the lts-group with a median overall survival of 36.0 months compared to 9.5 months in the sts-group. Demographics were comparable. The proteins most differentially expressed were isocitrate dehydrogenase 1 (IDH-1, 2.6-fold decreased in the lts-group compared to the sts-group) and ubiquitin conjugating enzyme E2 N (UBE2N, 2.3-fold decreased in the lts-group compared to the sts-group). In the naïve patients (n=12), UBE2N was similarly expressed in the lts- and sts-group (0.9-fold decrease in lts-group vs. sts-group). On the IHC stained slides, tumors in the lts-group expressed less UBE2N with a median H-score of 36 (range 0-234) compared to 134 (range 32-262) in the sts group (p=0.034).
Conclusion
While IDH-1 is a known target with a phase-1 trial recruiting, the role of UBE2N in pancreatic cancer as a potential response marker has not yet been described. Nevertheless, UBE2N is known to play a key role in the oncogenesis and chemoresistance of colorectal cancer, ovarian cancer, neuroblastoma, melanoma, hepatocellular carcinoma and prostate cancer. Our findings link UBE2N to survival after neoadjuvant treatment in pancreatic ductal adenocarcinoma and therefore reveal a promising new response marker.

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