Patients with advanced stages of
hepatocellular carcinoma (HCC) face a poor prognosis. Although encouraging clinical results have been obtained with multikinase inhibitor
sorafenib, the development of improved therapeutic strategies for HCC remains an urgent goal.
Aurora kinases are key regulators of the cell cycle, and their uncontrolled expression promotes
aneuploidy and
tumor development. In tissue microarray analyses, we detected
aurora-A kinase expression in all of the examined 93 human HCC samples, whereas
aurora-B kinase expression levels significantly correlated with the proliferation index of HCCs. In addition, two human HCC cell lines (Huh-7 and HepG2) were tested positive for aurora-A and -B and revealed Ser10 phosphorylation of
histone H3, indicating an increased
aurora-B kinase activity. The antiproliferative features of a novel
aurora kinase inhibitor,
PHA-739358, currently under investigation in phase 2 clinical trials for other solid
tumors, were examined in vitro and in vivo. At concentrations exceeding 50 nM,
PHA-739358 completely suppressed
tumor cell proliferation in cell culture experiments and strongly decreased
histone H3 phosphorylation. Cell cycle inhibition and endoreduplication were observed at 50 nM, whereas higher concentrations led to a complete G(2)/M-phase arrest. In vivo, administration of
PHA-739358 resulted in significant
tumor growth inhibition at a well-tolerated dose. In combination with
sorafenib, additive effects were observed. Remarkably, when
tumors restarted to grow under
sorafenib monotherapy, subsequent treatment with
PHA-739358 induced
tumor shrinkage by up to 81%. Thus, targeting
aurora kinases with
PHA-739358 is a promising therapeutic strategy administered alone or in combination with
sorafenib for patients with advanced stages of HCC.