Mahajan, Ujjwal M, Goni, Elisabetta, Langhoff, Enno, Li, Qi, Costello, Eithne, Greenhalf, William 
ORCID: 0000-0002-1865-3195, Kruger, Stephan, Ormanns, Steffen, Halloran, Christopher ORCID: 0000-0002-5471-4178, Ganeh, Paula et al (show 19 more authors)
(2020)
Cathepsin D Expression and Gemcitabine Resistance in Pancreatic Cancer.
JNCI CANCER SPECTRUM, 4 (1).
pkz060-.
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Abstract
<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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<sup>2</sup> <sub>LR, 1DF</sub> = 4.00; <i>P</i> = .04). Multivariable analysis revealed CatD expression as a predictive marker in gemcitabine-treated (z stat = 2.33; <i>P</i> = .02) but not in 5-fluorouracil-treated (z stat = 0.21; <i>P</i> = .82) patients. An independent validation cohort confirmed CatD as a negative predictive marker for survival (χ<sup>2</sup> <sub>LR, 1DF</sub> = 6.80; <i>P</i> = .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, <i>P</i> = .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.<h4>Conclusions</h4>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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Cancer, Pancreatic Cancer, Digestive Diseases, Rare Diseases, Cancer |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 22 Jun 2020 08:52 |
| Last Modified: | 15 Mar 2024 02:31 |
| DOI: | 10.1093/jncics/pkz060 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3091016 |
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