CES2 Expression in Pancreatic Adenocarcinoma Is Predictive of Response to Irinotecan and Is Associated With Type 2 Diabetes

Abstract

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.

CES2 sustains HNF4α expression to promote pancreatic adenocarcinoma progression through an epoxide hydrolase-dependent regulatory loop

“…Animal experiment protocols were reviewed and approved by The University of Texas MD Anderson Cancer Center IRB and in accordance with the Guidelines for the Care and Use of Laboratory Animals published by the NIH (Bethesda, MD). Detailed information regarding patient-derived xenografts (PDXs) is described in a prior publication [ 15 ]. For orthotopic xenograft models of PDAC and in vivo imaging, an enhanced GFP/firefly luciferase double-expressing cassette FG12 was introduced into AsPC-1 shCES2 or scramble control cells by lentiviral infection, as described previously [ 18 ].…”

“…The intrinsic role of CES2 in regulating lipid metabolism has been investigated in diabetes, liver steatosis, and nonalcoholic fatty liver disease [ [7] , [8] , [9] , [10] ]. To date, the relevance of CES2 in cancer has primarily been considered with respect to its functional role in mediating the activation of pro-drugs irinotecan and LY2334737 into their respective active forms [ 4 , 5 , [11] , [12] , [13] , [14] ], thereby providing a potential marker for predicting patient response to irinotecan- or LY2334737-containing regimens [ 2 , 5 , 15 , 16 ].…”

Langerhans islets induce anti-tumor immunity at the expense of glycemic control and predict chemotherapy response in pancreatic cancer

“…Our findings highlight that the presence of T2DM before the start of neoadjuvant chemotherapy as well as the dynamic of HbA1c levels during the treatment are markers for response to FOLFIRINOX. In line with this, another independent clinical investigation demonstrated that elevated HbA1c levels can be utilized as a marker for stratifying patients most likely to respond to FOLFIRINOX 51 .…”

“…While FOLFIRINOX is more effective than gemcitabine, the regimen also causes more side effects and significantly reduces quality of life of patients. However, response to chemotherapy varies, with only one third of patients responding to a specific regimen 51 . Given the fact that patients with unresponsiveness to neoadjuvant chemotherapy and irresectable PDA have a median life expectancy of less than a year preventing FOLFIRINOX-induced toxicity is an urgent clinical need.…”

SEOM clinical guidelines for pancreatic and biliary tract cancer (2020)

“…Serine hydrolase carboxylesterase 2 (CES2) is predictive of response to irinotecan as mediates its intra-tumoral activation. It is associated with type 2 diabetes [ 6 ].…”