Abstract
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.
Highlights
Hepatocellular carcinoma (HCC) is one of the most deadly cancers whose incidence follows a rising trend worldwide [1]
Drug-tolerant cell lines, SK-Suni and SK-HEP1-derived cells tolerant to sorafenib (SK-Sora), displayed a protein expression profile similar to the parental SKHEP1 but increased Smad3 and Smad4 expression as well as an exacerbated mesenchymal phenotype characterized by high c-MET expression; of note, SK-Suni displayed increased expression of the inhibitory Smad7 compared to SK-Sora (Figure 1A and 1B)
We showed that galunisertib displayed potent inhibition of canonical and noncanonical pathways in a variety of in vitro cell-lines models likely representing different types of HCC
Summary
Hepatocellular carcinoma (HCC) is one of the most deadly cancers whose incidence follows a rising trend worldwide [1] It is a disease with very few therapeutic options at advanced stage, in which sorafenib remains the only approved drug since 2007 based on the results of two randomized studies [2, 3]. TGF-β pathway has gained considerable interest due to its pleiotropic role in regulating cell growth, differentiation, apoptosis, and motility at the tumor level, as well as extracellular matrix production, angiogenesis, and cellular immune response at the tumor microenvironment level [4,5,6]. At Smad levels, TGF-β pathway integrates signaling from integrins, Notch, Wnt, TNF-α, or EGF-dependent pathways as well as signals from cellular processes such as the cell-cycle or apoptosis machineries
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
