Everolimus Augments the Effects of Sorafenib in a Syngeneic Orthotopic Model of Hepatocellular Carcinoma

Abstract

Sorafenib targets the Raf/mitogen-activated protein kinase, VEGF, and platelet-derived growth factor pathways and prolongs survival patients in advanced hepatocellular carcinoma (HCC). Everolimus inhibits the mammalian target of rapamycin, a kinase overactive in HCC. To investigate whether the antitumor effects of these agents are additive, we compared a combined and sequential treatment regimen of everolimus and sorafenib with monotherapy. After hepatic implantation of Morris Hepatoma (MH) cells, rats were randomly allocated to everolimus (5 mg/kg, 2Â/week), sorafenib (7.5 mg/kg/d), combined everolimus and sorafenib, sequential sorafenib (2 weeks) then everolimus (3 weeks), or control groups. MRI quantified tumor volumes. Erk1/2, 4E-BP1, and their phosphorylated forms were quantified by immunoblotting. Angiogenesis was assessed in vitro by aortic ring and tube formation assays, and in vivo with Vegf-a mRNA and vascular casts. After 35 days, tumor volumes were reduced by 60%, 85%, and 55%, relative to controls, in everolimus, the combination, and sequential groups, respectively (P < 0.01). Survival was longest in the combination group (P < 0.001). Phosphorylation of 4E-BP1 and Erk1/2 decreased after everolimus and sorafenib, respectively. Angiogenesis decreased after all treatments (P < 0.05), although sorafenib increased Vegf-a mRNA in liver tumors. Vessel sprouting was abundant in control tumors, lower after sorafenib, and absent after the combination. Intussusceptive angiogenic transluminal pillars failed to coalesce after the combination. Combined treatment with everolimus and sorafenib exerts a stronger antitumoral effect on MH tumors than monotherapy. Everolimus retains antitumoral properties when administered sequentially after sorafenib. This supports the clinical use of everolimus in HCC, both in combination with sorafenib or after sorafenib.

Inhibition of Akt Reverses the Acquired Resistance to Sorafenib by Switching Protective Autophagy to Autophagic Cell Death in Hepatocellular Carcinoma

“…Many lines of studies have shown that sorafenib activates the PI3K/Akt pathway (7,8,18,30), and blockage of this pathway enhances the efficacy of sorafenib (7,30), but it has also been reported that sorafenib enhances proteasome inhibitor-induced cell death by inactivating Akt in HCC (31), indicating that the complicated role of the PI3K/Akt pathway in sorafenib resistance is far from clear. Here, we have demonstrated that Akt was activated in sorafenib-resistant cells, in accordance with a previous report (9).…”

A Phase II Study of Sorafenib in Patients with Platinum-Pretreated, Advanced (Stage IIIb or IV) Non–Small Cell Lung Cancer with a KRAS Mutation

“…PI3K actually is partially dependent on RAS signaling (28,29). Preclinical studies have shown synergistic effects in mice with a combination of everolimus (mTOR inhibitor) and sorafenib (30). Phase I studies in renal cell and hepatocellular cancer have shown that the combination of everolimus and sorafenib was active and tolerable (31)(32)(33).…”

Current and Future Treatment Strategies for Patients with Advanced Hepatocellular Carcinoma: Role of mTOR Inhibition

“…In human HCC cell lines, everolimus, sirolimus, and temsirolimus have been shown to inhibit cell growth and proliferation [14,[16][17][18][19]. In various HCC mouse and rat models, everolimus and sirolimus significantly reduced tumor volume and angiogenesis, delayed tumor growth, and increased overall survival compared with control [16][17][18][19][20].…”