Carboxylesterase 2 as a Determinant of Response to Irinotecan and Neoadjuvant FOLFIRINOX Therapy in Pancreatic Ductal Adenocarcinoma.

Abstract

BACKGROUND:

Serine hydrolases (SHs) are among the largest classes of enzymes in humans and play crucial role in many pathophysiological processes of cancer. We have undertaken a comprehensive proteomic analysis to assess the differential expression and cellular localization of SHs, which uncovered distinctive expression of Carboxylesterase 2 (CES2), the most efficient carboxyl esterase in activating the prodrug irinotecan into SN-38, in pancreatic ductal adenocarcinoma (PDAC). We therefore assessed the extent of heterogeneity in CES2 expression in PDAC and its potential relevance to irinotecan based therapy.

METHODS:

CES2 expression in PDAC and paired nontumor tissues was evaluated by immunohistochemistry. CES2 activity was assessed by monitoring the hydrolysis of the substrate p-NPA and correlated with irinotecan IC50 values by means of Pearson's correlation. Kaplan-Meier and Cox regression analyses were applied to assess the association between overall survival and CES2 expression in patients who underwent neoadjuvant FOLFIRINOX treatment. All statistical tests were two-sided.

RESULTS:

Statistically significant overexpression of CES2, both at the mRNA and protein levels, was observed in PDAC compared with paired nontumor tissue (P < .001), with 48 of 118 (40.7%) tumors exhibiting high CES2 expression. CES2 activity in 11 PDAC cell lines was inversely correlated with irinotecan IC50 values (R = -0.68, P = .02). High CES2 expression in tumor tissue was associated with longer overall survival in resectable and borderline resectable patients who underwent neoadjuvant FOLFIRINOX treatment (hazard ratio = 0.14, 95% confidence interval = 0.04 to 0.51, P = .02).

CONCLUSION:

Our findings suggest that CES2 expression and activity, by mediating the intratumoral activation of irinotecan, is a contributor to FOLFIRINOX sensitivity in pancreatic cancer and CES2 assessment may define a subset of patients likely to respond to irinotecan based therapy.

• Authors: Michela Capello, Minhee Lee, Hong Wang, Ingrid Babel, Matthew H Katz, Jason B Fleming, Anirban Maitra, Huamin Wang, Weihua Tian, Ayumu Taguchi, Samir M Hanash
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 107 Issue 8 (Aug 2015) ISSN: 1460-2105 [Electronic] United States
• PMID: 26025324 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: [email protected].

Chemical References

• Organoplatinum Compounds
• RNA, Messenger
• Oxaliplatin
• Irinotecan
• CES2 protein, human
• Carboxylesterase
• Fluorouracil
• Camptothecin

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Camptothecin (administration & dosage, analogs & derivatives)
• Carboxylesterase (genetics, metabolism)
• Carcinoma, Pancreatic Ductal (drug therapy, enzymology)
• Cell Line, Tumor
• Chemotherapy, Adjuvant
• Female
• Fluorouracil (administration & dosage)
• Humans
• Immunohistochemistry
• Irinotecan
• Kaplan-Meier Estimate
• Male
• Mass Spectrometry
• Middle Aged
• Neoadjuvant Therapy (methods)
• Organoplatinum Compounds (administration & dosage)
• Oxaliplatin
• Pancreatic Neoplasms (drug therapy, enzymology)
• RNA, Messenger (metabolism)
• Radiotherapy, Adjuvant
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Sequence Analysis, RNA
• Tissue Array Analysis
• Treatment Outcome
• Xenograft Model Antitumor Assays