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P06.07-YI

AKT INHIBITOR ARQ 092 AND SORAFENIB ADDITIVELY
INHIBIT PROGRESSION OF HEPATOCELLULAR
CARCINOMA AND IMPROVE IMMUNE SYSTEM IN
CIRRHOTIC RAT MODEL

Zuzana Macek Jilkova * 1, 2 , Ayca Zeybek Kuyucu 1, 2, 3 , Keerthi Kurma 1, 2 , Séyédéh
Tayébéh Ahmad Pour , Gael S. Roth 1, 2, 4 , Giovanni Abbadessa , Yi Yu , Vincent
1, 2
5
5
Leroy 1, 2, 4 , Patrice Marche , Thomas Decaens 1, 2, 4
1, 2
2
1 Université Grenoble Alpes, Institute for Advanced Biosciences, Research Center UGA / Inserm
3
4
U 1209 / CNRS 5309, Grenoble, France, Izmir Institute of Technology, Izmir, Turkey, Clinique
Universitaire d’Hépato-gastroentérologie, Grenoble, France, ArQule Inc, Burlington, MA,
5
United States
Corresponding author’s email: zuzana.macek-jilkova@inserm.fr
Introduction: Longer exposure to classical treatment of advanced hepatocellular
carcinoma (HCC), sorafenib, often over-activates AKT pathway, leading to HCC
resistance. Moreover, AKT pathway itself is activated in almost half of HCC cases. ePOSTER ABSTRACTS
Aims: We investigated the efficacy of combination of sorafenib with allosteric Akt inhibitor
ARQ 092 in a diethylnitrosamine (DEN)-induced cirrhotic rat model with HCC.

Material and Methods: 28 rats were DEN-injured during 14 weeks to obtain cirrhosis
with fully developed HCC, then randomized into 4 groups: control, sorafenib, ARQ
092 or combination of ARQ 092+sorafenib; (n=7/group) and treated for 6 weeks.
Tumor progression was followed by MRI every 3 weeks. Pathological analysis and
immunohistochemistry were blindly analysed. Flow cytometry analyses, RT-PCR, and
western-blot were performed.

Results: Tumor progression was significantly reduced by combination treatment (53
%) compared to the control (158 %; p<0.0001) sorafenib (106 %; p=0.006) or ARQ
092 group (105 %; p=0.010). Mean number of tumors was lower in combination
group (n=21.2) when compared to the control (n=100.4; p<0.0001) or sorafenib group
(n=69.2; p=0.002). Similarly, tumor mean size was significantly reduced in combination
group (3.1 mm) compared to the control group (9.9 mm; p<0.0001), sorafenib group (6.4
mm; p=0.019) or ARQ 092 group (6.3 mm; p=0.031). Tumor decrease was associated
with a significant reduction in tumor cell proliferation and an increased apoptosis. CD34

EASL HCC Summit • Geneva, Switzerland • 2-5 February, 2017 235