Journal
ONCOTARGET
Volume 6, Issue 13, Pages 10853-10867Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.3414
Keywords
ErbB2; pancreatic cancer; gemcitabine; FOLFIRINOX; chemoresistance
Categories
Funding
- Centre Hospitalier Regional et Universitaire (CHRU) de Lille/region Nord-Pas de Calais
- Universite de Lille 2
- Fondation ARC
- Region Nord-Pas de Calais
- la Ligue Nationale Contre le Cancer (Equipe Labellisee Ligue)
- SIRIC ONCOLille
- Grant INCaDGOS-Inserm [6041]
- Contrat de Plan Etat Region CPER Cancer
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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-kappa B 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.
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