MULTILAYERED VALIDATION OF ABCC4/MRP4 AS A THERAPEUTIC TARGET FOR PANCREATIC CANCER

CAROZZO, A; ABBA, M; MOHR, N; SHAYO, C; GOMEZ, N; MAY, M; YANEFF, A; ITURBE, J; MONCZOR, F; FERNANDEZ, N; DAVIO, C

Congreso; LXI REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA; 2016

Pancreatic ductal adenocarcinoma (PDAC) is one of the most severe typesof cancer, and because of its early development of resistance to standardtherapeutic agents, and its late diagnosis, it results imperative to identifyand validate new and key therapeutic targets. A lot of evidence implicatesdisturbances in cAMP cascade with PDAC, suggesting the oncogenic potential of thissignaling pathway in this setting. In addition to the known classicalmechanisms of regulation of cAMP, it was recently described its extrusion tothe extracellular compartment mediated by MRP4. The aim of the present work wasto validate MRP4 as a therapeutic target and characterize the role of cAMPextrusion in PDAC progression. The analysis of MRP4 expression profiles inhuman PDAC samples indicated higher levels of expression in tumor cells (normaltissue vs primary tumor; p<0,01). We also determined an inverse relationshipbetween MRP4 expression and the probability of survival of patients, establishinga clear association between the staining intensity of MRP4 and Ki67. Thissuggests the existence of a subset of cells within the tumor that are actively proliferatingand express higher levels of MRP4. In vitro assays in PDAC cell lines (PANC-1,BxPC3 and HPAFII) demonstrated a positive correlation between MRP4 expression,cell indifferentiation and cAMP extrusion. Pharmacological inhibition of MRP4,as well as its specific knockdown by shRNA, led to a significant decrease ofcell migration and proliferation (p<0,01), the latter by regulating cellcycle progression in G1/S. Both effects were reversed by inhibition of thecAMP-dependant Epac/ Rap1 cascade or by adding cAMP acting through a still unknownreceptor. Furthermore, silencing MRP4 strongly reduced tumor growth andincidence in nude and NSG animal models. Altogether, these results validateMRP4 as a new therapeutic target for PDAC and demonstrate the oncogenicpotential of cAMPextrusion.