Research Papers:

Effects of TGF-beta signalling inhibition with galunisertib (LY2157299) in hepatocellular carcinoma models and in ex vivo whole tumor tissue samples from patients

Maria Serova, Annemilaï Tijeras-Raballand, Célia Dos Santos, Miguel Albuquerque, Valerie Paradis, Cindy Neuzillet, Karim A. Benhadji, Eric Raymond, Sandrine Faivre and Armand de Gramont _

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Oncotarget. 2015; 6:21614-21627. https://doi.org/10.18632/oncotarget.4308

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Maria Serova1,2, Annemilaï Tijeras-Raballand1,2, Célia Dos Santos1,2, Miguel Albuquerque3, Valerie Paradis3, Cindy Neuzillet2, Karim A. Benhadji4, Eric Raymond2, Sandrine Faivre2,3 and Armand de Gramont1,2

1 AAREC Filia Research, Boulogne-Billancourt, France

2 INSERM U728, Department of Medical Oncology, Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), Clichy, France

3 INSERM U773, Department of Pathology, Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), Clichy, France

4 Eli Lilly and Co, Neuilly-sur-Seine, France

Correspondence to:

Armand de Gramont, email:

Keywords: TGF-β inhibition, hepatocellular carcinoma, galunisertib, sorafenib, SMAD

Received: August 06, 2014 Accepted: May 12, 2015 Published: May 27, 2015


Galunisertib (LY2157299) is a selective ATP-mimetic inhibitor of TGF-β receptor (TβR)-I activation currently under clinical investigation in hepatocellular carcinoma (HCC) patients. Our study explored the effects of galunisertib in vitro in HCC cell lines and ex vivo on patient samples. Galunisertib was evaluated in HepG2, Hep3B, Huh7, JHH6 and SK-HEP1 cells as well as in SK-HEP1-derived cells tolerant to sorafenib (SK-Sora) and sunitinib (SK-Suni). Exogenous stimulation of all HCC cell lines with TGF-β yielded downstream activation of p-Smad2 and p-Smad3 that was potently inhibited with galunisertib treatment at micromolar concentrations. Despite limited antiproliferative effects, galunisertib yielded potent anti-invasive properties. Tumor slices from 13 patients with HCC surgically resected were exposed ex vivo to 1 µM and 10 µM galunisertib, 5 µM sorafenib or a combination of both drugs for 48 hours. Galunisertib but not sorafenib decreased p-Smad2/3 downstream TGF-β signaling. Immunohistochemistry analysis of galunisertib and sorafenib-exposed samples showed a significant decrease of the proliferative marker Ki67 and increase of the apoptotic marker caspase-3. In combination, galunisertib potentiated the effect of sorafenib efficiently by inhibiting proliferation and increasing apoptosis. Our data suggest that galunisertib may be active in patients with HCC and could potentiate the effects of sorafenib.

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