TY - JOUR
T1 - CES2 expression in pancreatic adenocarcinoma is predictive of response to irinotecan and is associated with type 2 diabetes
AU - Capello, Michela
AU - Fahrmann, Johannes F.
AU - Rios Perez, Mayrim V.
AU - Vykoukal, Jody V.
AU - Irajizad, Ehsan
AU - Tripathi, Satyendra C.
AU - Roife, David
AU - Bantis, Leonidas E.
AU - Kang, Yaan
AU - Kundnani, Deepali L.
AU - Xu, Hanwen
AU - Prakash, Laura R.
AU - Long, James P.
AU - Katayama, Hiroyuki
AU - Fleury, Alia
AU - Ferri-Borgogno, Sammy
AU - Baluya, Dodge L.
AU - Dennison, Jennifer B.
AU - Aguilar-Bonavides, Clemente
AU - Casabar, Julian P.
AU - Celiktas, Muge
AU - Do, Kim Anh
AU - Fiehn, Oliver
AU - Maitra, Anirban
AU - Wang, Huamin
AU - Feng, Ziding
AU - Chiao, Paul J.
AU - Katz, Matthew H.
AU - Fleming, Jason B.
AU - Hanash, Samir M.
N1 - Publisher Copyright:
© 2020 by American Society of Clinical Oncology
PY - 2019
Y1 - 2019
N2 - PURPOSE The combination chemotherapy of fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) has provided clinically meaningful improvement for pancreatic ductal adenocarcinoma (PDAC). We previously uncovered a role for the serine hydrolase carboxylesterase 2 (CES2) in mediating intratumoral activation of the prodrug irinotecan, a constituent of FOLFIRINOX. We aimed to further test the predictive value of CES2 for response to irinotecan using patient-derived xenograft (PDX) models and to elucidate the determinants of CES2 expression and response to FOLFIRINOX treatment among patients with PDAC. 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.
AB - PURPOSE The combination chemotherapy of fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) has provided clinically meaningful improvement for pancreatic ductal adenocarcinoma (PDAC). We previously uncovered a role for the serine hydrolase carboxylesterase 2 (CES2) in mediating intratumoral activation of the prodrug irinotecan, a constituent of FOLFIRINOX. We aimed to further test the predictive value of CES2 for response to irinotecan using patient-derived xenograft (PDX) models and to elucidate the determinants of CES2 expression and response to FOLFIRINOX treatment among patients with PDAC. 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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U2 - 10.1200/PO.19.00330
DO - 10.1200/PO.19.00330
M3 - Article
C2 - 35050739
AN - SCOPUS:85086452805
SN - 2473-4284
VL - 3
SP - 426
EP - 436
JO - JCO Precision Oncology
JF - JCO Precision Oncology
ER -