Abstract
Advanced hepatocarcinoma (HCC) is an aggressive malignancy with poor prognosis and limited treatment options. Alterations of the cyclin D-CDK4/6-Rb pathway occur frequently in HCC, providing the rationale for its targeting at least in a molecular subset of HCC. In a panel of HCC cell lines, we investigated whether the CDK4/6 inhibitor palbociclib might improve the efficacy of regorafenib, a powerful multi-kinase inhibitor approved as second-line treatment for advanced HCC after sorafenib failure and currently under clinical investigation as first-line therapy in combination with immunotherapy. In Rb-proficient cells, the simultaneous drug combination, but not the sequential schedules, inhibited cell proliferation, either in short or in long-term experiments, and induced cell death more strongly than individual treatments. Moreover, the combination significantly reduced spheroid cell growth and inhibited cell migration/invasion. The superior efficacy of palbociclib plus regorafenib emerged also under hypoxia and was associated with a significant down-regulation of CDK4/6-Rb-myc and mTORC1/p70S6K signaling. Moreover, regorafenib suppressed palbociclib-induced expression of cyclin D1 contributing to the cytotoxic effects of the combination. Besides these inhibitory effects on cell viability/proliferation, palbociclib and regorafenib reduced glucose uptake, although this effect was dependent on the cell model and on the oxygen availability (normoxia or hypoxia). Palbociclib and regorafenib combination impaired glucose uptake and utilization, down-regulating basal and hypoxia-induced expression of HIF-1α, HIF-2α, GLUT-1, and MCT4 proteins as well as the activity/expression of glycolytic enzymes (HK2, PFKP, aldolase A, PKM2). In addition, regorafenib alone reduced mitochondrial respiration. The combined treatment impaired glucose metabolism and respiration without enhancing the effects of the single agents. Our findings provide pre-clinical evidence for the effectiveness of palbociclib and regorafenib combination in HCC cell models.
Highlights
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, sixth most common cancer, and third leading cause of cancer deaths worldwide [1, 2]
We evaluated the effects of palbociclib on cell proliferation in a panel of HCC cell lines
These results are in line with previous pre-clinical studies showing that cyclin D1 expression and the loss of p16INK4a correlate with a superior efficacy of cyclin dependent kinase 4/6 (CDK4/6) inhibitors in breast cancer cells [29,30,31]
Summary
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, sixth most common cancer, and third leading cause of cancer deaths worldwide [1, 2]. Systemic therapy remains the only available therapeutic option for advanced HCC. Sorafenib has been the only global first-line standard of care for advanced HCC until the recent Food and Drug Administration (FDA) first-line approval of the multi-kinase inhibitor lenvatinib [4]. Other targeted drugs became available as secondline treatment options, i.e., the tyrosine kinase inhibitors (TKIs) cabozantinib and ramucirumab [6], and the immune checkpoint inhibitors nivolumab and pembrolizumab in the US [6,7,8]. The combined use of atezolizumab, another immune checkpoint inhibitor (anti-PD-L1), and the anti-VEGF bevacizumab has been reported to be superior to sorafenib in a multicenter global phase III clinical trial (IMbrave150, NCT03434379) and FDA is considering this association as first-line treatment in HCC [9]. There is an urgent need for the identification of novel candidate targets for HCC therapy
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