Cathepsin D Expression and Gemcitabine Resistance in Pancreatic Cancer


Mahajan, U. M., Goni, E., Langhoff, E., Li, Q., Costello, E., Greenhalf, W., Kruger, S., Ormanns, S., Halloran, C., Ganeh, P., Marron, M., Lammerhirt, F., Zhao, Y., Beyer, G., Weiss, F. U., Sendler, M., Bruns, C. J., Kohlmann, T., Kirchner, T., Werner, J., D'Haese, J. G., von Bergwelt-Baildon, M., Heinemann, V., Neoptolemos, J. P., Buchler, M. W., Belka, C., Boeck, S., Lerch, M. M., and Mayerle, J. (2020). JNCI Cancer Spectr 4, pkz060



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.