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Cathepsin D Expression and Gemcitabine Resistance in Pancreatic Cancer.

Authors :: Mahajan UM
Goni E
Langhoff E
Li Q
Costello E
Greenhalf W
Kruger S
Ormanns S
Halloran C
Ganeh P
Marron M
Lämmerhirt F
Zhao Y
Beyer G
Weiss FU
Sendler M
Bruns CJ
Kohlmann T
Kirchner T
Werner J
D'Haese JG
von Bergwelt-Baildon M
Heinemann V
Neoptolemos JP
Büchler MW
Belka C
Boeck S
Lerch MM
Mayerle J
Source :: JNCI cancer spectrum [JNCI Cancer Spectr] 2019 Aug 16; Vol. 4 (1), pp. pkz060. Date of Electronic Publication: 2019 Aug 16 (Print Publication: 2020).
Publication Year :: 2019
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.<br />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.<br />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 <superscript>2</superscript> <subscript>LR, 1DF</subscript> = 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 <superscript>2</superscript> <subscript>LR, 1DF</subscript> = 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.<br />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.<br /> (© The Author(s) 2020. Published by Oxford University Press.)