CES2 Expression in Pancreatic Adenocarcinoma Is Predictive of Response to Irinotecan and Is Associated With Type 2 Diabetes.
Abstract | PURPOSE: METHODS: PDXs were engrafted subcutaneously into nude mice and treated for 4 weeks with either saline control or irinotecan. CES2 and hepatocyte nuclear factor 4 alpha (HNF4A) expression in PDAC tissues was evaluated by immunohistochemical and Western blot analysis. Kaplan-Meier and Cox regression analyses were applied to assess the association between overall survival and hemoglobin A1C (HbA1C) levels in patients who underwent neoadjuvant FOLFIRINOX treatment. RESULTS: High CES2 activity in PDAC PDXs was associated with increased sensitivity to irinotecan. Integrated gene expression, proteomic analyses, and in vitro genetic experiments revealed that nuclear receptor HNF4A, which is upregulated in diabetes, is the upstream transcriptional regulator of CES2 expression. Elevated CES2 protein expression in PDAC tissues was positively associated with a history of type 2 diabetes (odds ratio, 4.84; P = .02). High HbA1C levels were associated with longer overall survival in patients who received neoadjuvant FOLFIRINOX treatment (P = .04). CONCLUSION: To our knowledge, we provide, for the first time, evidence that CES2 expression is associated with a history of type 2 diabetes in PDAC and that elevated HbA1C, by predicting tumor CES2 expression, may represent a novel marker for stratifying patients most likely to respond to FOLFIRINOX therapy.
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Authors | Michela Capello, Johannes F Fahrmann, Mayrim V Rios Perez, Jody V Vykoukal, Ehsan Irajizad, Satyendra C Tripathi, David Roife, Leonidas E Bantis, Ya'an Kang, Deepali L Kundnani, Hanwen Xu, Laura R Prakash, James P Long, Hiroyuki Katayama, Alia Fleury, Sammy Ferri-Borgogno, Dodge L Baluya, Jennifer B Dennison, Clemente Aguilar-Bonavides, Julian P Casabar, Muge Celiktas, Kim-Anh Do, Oliver Fiehn, Anirban Maitra, Huamin Wang, Ziding Feng, Paul J Chiao, Matthew H Katz, Jason B Fleming, Samir M Hanash |
Journal | JCO precision oncology
(JCO Precis Oncol)
Vol. 4
Pg. 426-436
(Nov 2020)
ISSN: 2473-4284 [Electronic] United States |
PMID | 35050739
(Publication Type: Journal Article)
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