Cathepsin D Expression and Gemcitabine Resistance in Pancreatic Cancer. Issue 1 (16th August 2019)

• Record Type: Journal Article
• Authors: Mahajan, Ujjwal M; Goni, Elisabetta; Langhoff, Enno; Li, Qi; Costello, Eithne; Greenhalf, William; Kruger, Stephan; Ormanns, Steffen; Halloran, Christopher; Ganeh, Paula; Marron, Manuela; Lämmerhirt, Felix; Zhao, Yue; Beyer, Georg; Weiss, Frank-Ulrich; Sendler, Matthias; Bruns, Christiane J; Kohlmann, Thomas; Kirchner, Thomas; Werner, Jens; D'Haese, Jan G; von Bergwelt-Baildon, Michael; Heinemann, Volker; Neoptolemos, John P; Büchler, Markus W; Belka, Claus; Boeck, Stefan; Lerch, Markus M; Mayerle, Julia
• Is Part Of: JNCI cancer spectrum. Volume 4:Issue 1(2020)
• Publication Date: 2019-08-16
• DOI: 10.1093/jncics/pkz060
• Languages: English
• ISSNs: 2515-5091

Abstract

Abstract: Background: Cathepsin-D (CatD), owing to its dual role as a proteolytic enzyme and as a ligand, has been implicated in cancer progression. The role of CatD in pancreatic ductal adenocarcinoma is unknown. Methods: CatD expression quantified by immunohistochemistry of tumor-tissue microarrays of 403 resected pancreatic cancer patients from the ESPAC-Tplus trial, a translational study within the ESPAC (European Study Group for Pancreatic Cancer) trials, was dichotomously distributed to low and high H scores (cut off 22.35) for survival and multivariable analysis. The validation cohort (n = 69) was recruited based on the hazard ratio of CatD from ESPAC-Tplus. 5-fluorouracil-, and gemcitabine-resistant pancreatic cancer cell lines were employed for mechanistic experiments. All statistical tests were two-sided. Results: Median overall survival was 23.75 months and median overall survival for patients with high CatD expression was 21.09 (95% confidence interval [CI] = 17.31 to 24.80) months vs 27.20 (95% CI = 23.75 to 31.90) months for low CatD expression (χ 2 LR, 1DF = 4.00; P = .04). Multivariable analysis revealed CatD expression as a predictive marker in gemcitabine-treated (z stat = 2.33; P = .02) but not in 5-fluorouracil-treated (z stat = 0.21; P = .82) patients. An independent validation cohort confirmed CatD as a negative predictive marker for survival (χ 2 LR, 1DF = 6.80; P = .009) and as an independent predictive marker in gemcitabine-treated patients with a hazard ratio of 3.38 (95% CI = 1.36 to 8.38, P = .008). Overexpression of CatD was associated with a concomitant suppression of the acid sphingomyelinase, and silencing of CatD resulted in upregulation of acid sphingomyelinase with rescue of gemcitabine resistance. Conclusions: Adjuvant gemcitabine is less effective in pancreatic ductal adenocarcinoma with high CatD expression, and thus CatD could serve as a marker for biomarker-driven therapy.