Cathepsin D Expression and Gemcitabine Resistance in Pancreatic Cancer.

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 (χ2 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 (χ2 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.

• Authors: Ujjwal M Mahajan, Elisabetta Goni, Enno Langhoff, Qi Li, Eithne Costello, William Greenhalf, Stephan Kruger, Steffen Ormanns, Christopher Halloran, Paula Ganeh, Manuela Marron, Felix Lämmerhirt, Yue Zhao, Georg Beyer, Frank-Ulrich Weiss, Matthias Sendler, Christiane J Bruns, Thomas Kohlmann, Thomas Kirchner, Jens Werner, Jan G D'Haese, Michael von Bergwelt-Baildon, Volker Heinemann, John P Neoptolemos, Markus W Büchler, Claus Belka, Stefan Boeck, Markus M Lerch, Julia Mayerle
• Journal: JNCI cancer spectrum (JNCI Cancer Spectr) Vol. 4 Issue 1 Pg. pkz060 (Feb 2020) ISSN: 2515-5091 [Electronic] England
• PMID: 32296755 (Publication Type: Journal Article)
• Copyright: © The Author(s) 2020. Published by Oxford University Press.