Chloroquine plays a cell-dependent role in the response to treatment of pancreatic adenocarcinoma

// Maria Ines Molejon 1, 2, * , Mirna Swayden 1, * , Daniele Fanale 3 , Jennifer Bintz 1 , Odile Gayet 1 , Philippe Soubeyran 1 and Juan Iovanna 1 1 Centre de Recherche en Cancerologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Universite and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France 2 INCITAP-CONICET (Instituto de Ciencias de la Tierra y Ambientales - Consejo Nacional de Investigaciones Cientificas y Tecnicas), Facultad de Ciencias Exactas y Naturales, Universidad Nacional de La Pampa (UNLPam), Santa Rosa, La Pampa, Argentina 3 Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy * These authors have contributed equally to this work Correspondence to: Juan Iovanna, email: juan.iovanna@inserm.fr Keywords: pancreas cancer; autophagy; Chloroquine; gemcitabine Received: April 23, 2018      Accepted: June 23, 2018      Published: July 20, 2018 ABSTRACT In this study, our aim is to assess the role played by autophagy and its inhibition in the different PDAC cellular compartments, and its involvement in chemo-resistance using primary human pancreatic cancer-derived cells (PCC) and Cancer Associated Fibroblasts (CAF). Autophagy flux, as measured by LC3-I and -II in the presence of Chloroquine, showed a variable level in PCC and CAFs. We found no correlation between autophagy level and degree of tumor differentiation. Association of Chloroquine with gemcitabine, 5FU, oxaliplatin, irinotecan and docetaxel revealed that its effect on survival is cell- and drug-dependent in vitro and in vivo . In addition, we demonstrated that autophagy in CAFs can play an important role in sensitizing PDAC to anticancer treatments since its inhibition increased the resistance of PCCs to gemcitabine. In conclusion, this work clearly shows a heterogeneity in the effect of Chloroquine and highlights a role of CAFs autophagy in sensitizing tumors to treatments. It also reveals that the role of autophagy is more complex than expected in PDAC as well as its sensitivity to treatments.