The oncogenic receptor ErbB2 modulates gemcitabine and irinotecan/SN-38 chemoresistance of human pancreatic cancer cells via hCNT1 transporter and multidrug-resistance associated protein MRP-2

// Nicolas Skrypek 1, 2, 3 , Romain Vasseur 1, 2, 3 , Audrey Vincent 1, 2, 3 , Belinda Duchene 1, 2, 3 , Isabelle Van Seuningen 1, 2, 3 , Nicolas Jonckheere 1, 2, 3 1 Inserm, UMR-S1172, Jean Pierre Aubert Research Center, Team #5 “Mucins, epithelial differentiation and carcinogenesis”, Lille cedex 59045, France 2 Universite Lille Nord de France, Lille cedex 59000, France 3 Centre Hospitalier Regional et Universitaire de Lille, Lille cedex 59037, France Correspondence to: Nicolas Jonckheere, e-mail: nicolas.jonckheere@inserm.fr Keywords: ErbB2, pancreatic cancer, gemcitabine, FOLFIRINOX, chemoresistance Received: November 18, 2014      Accepted: February 19, 2015      Published: March 26, 2015 ABSTRACT Pancreatic adenocarcinoma (PDAC) is one of the most deadly cancers because of a lack of early diagnotic markers and efficient therapeutics. The fluorinated analog of deoxycytidine, gemcitabine and emerging FOLFIRINOX protocol (5-fluorouracil (5-FU), irinotecan/SN-38, oxaliplatin and leucovorin) are the main chemotherapies to treat PDAC. The ErbB2/HER2 oncogenic receptor is commonly overexpressed in PDAC. In this context, we aimed to decipher the ErbB2-mediated mechanisms of chemoresistance to the two main chemotherapy protocols used to treat PDAC. ErbB2 knocking down (KD) in CAPAN-1 and CAPAN-2 cells led to an increased sensitivity to gemcitabine and an increased resistance to irinotecan/SN-38 both in vitro and in vivo (subcuteanous xenografts) This was correlated to an increase of hCNT1 and hCNT3 transporters and ABCG2, MRP1 and MRP2 ATP-binding cassette transporters expression and resistance to cell death. We also show that MRP2 is repressed following activation of JNK, Erk1/2 and NF-κB pathways by ErbB2. Finally, in datasets of human PDAC samples, ErbB2 and MRP2 expression was conversely correlated. Altogether, we propose that ErbB2 mediates several intracellular mechanisms linked to PDAC cell chemoresistance that may represent potential targets in order to ameliorate chemotherapy response and allow stratification of patients eligible for either gemcitabine or FOLFIRINOX treatment.