Abstract
Sorafenib is the standard first-line systemic drug for advanced hepatocellular carcinoma (HCC), but the acquired resistance to sorafenib results in limited benefits. Activation of Akt is thought to be responsible for mediating the acquired resistance to sorafenib. The present study aims to examine the underlying mechanism and seek potential strategies to reverse this resistance. Two sorafenib-resistant HCC cell lines, which had been established from human HCC HepG2 and Huh7 cells, were refractory to sorafenib-induced growth inhibition and apoptosis in vitro and in vivo. Sustained exposure to sorafenib activated Akt via the feedback loop of mTOR but independent of protein phosphatase 2A in HCC cells. Autophagy participated in the resistance to sorafenib as inhibition of autophagy reduced the sensitivity of sorafenib-resistant HCC cells to sorafenib, whereas activation of autophagy by rapamycin had the opposite effect. However, rapamycin did not show a synergistic effect with sorafenib to inhibit cell proliferation, while it also activated Akt via a feedback mechanism in sorafenib-resistant HCC cells. Inhibition of Akt reversed the acquired resistance to sorafenib by switching autophagy from a cytoprotective role to a death-promoting mechanism in the sorafenib-resistant HCC cells. Akt inhibition by GDC0068 synergized with sorafenib to suppress the growth of sorafenib-resistant HCC tumors that possessed the sorafenib-resistant feature in vivo. The results have provided evidence for clinical investigation of GDC0068, a novel ATP-competitive pan-Akt inhibitor, as the second-line treatment after the failure of sorafenib-medicated molecular targeted therapy for advanced HCC.
Highlights
Hepatocellular carcinoma (HCC), the second most frequent cause of cancer death in men worldwide [1], is notoriously resistant to systemic chemotherapy [2]
The antibodies (Abs) against Akt, phosphorylated Akt (p-Akt) (Ser473), extracellular signaling-regulated kinase (ERK), p-ERK (Thr202/Thyr204), glycogen synthase kinase (GSK)-3b, phosphorylated GSK3b, mTOR, S6 kinase (S6K), phosphorylated S6K (p-S6K; Thr389), 4E-binding protein 1 (4EBP1), phosphorylated 4EBP1 (p-4EBP1; Ser65), PARP, LC3, Beclin1, ATG5, class III phosphoinositide 3-kinase (PI3K) vascular protein sorting 34 (Vps34), UV radiation resistance-associated gene (UVRAG), and p62 were purchased from Cell Signaling Technology
Sorafenib-resistant HCC cells are refractory to sorafenib-induced growth inhibition and apoptosis
Summary
Hepatocellular carcinoma (HCC), the second most frequent cause of cancer death in men worldwide [1], is notoriously resistant to systemic chemotherapy [2]. As a multitargeted kinase inhibitor, sorafenib targets the Raf/mitogen-activated protein kinase (MAPK)/extracellular signaling-regulated kinase (ERK) signaling pathway, and inhibits a number of tyrosine kinase receptors, including VEGF receptor, platelet-derived growth factor receptor, and c-Kit [3]. The phosphoinositide 3-kinase (PI3K)/Akt pathway regulates a large number of molecules involved in all aspects of cancer progression [5], and is involved in the development and progression of HCC [6]. Sorafenib activates Akt and upregulates its downstream factors such as ribosomal protein S6 kinase (S6K) and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) in HCC cells [7, 8]. There exist cross-talks between the PI3K/Akt and MAPK/ERK pathways [10], indicating that the latent compensatory mechanism of the PI3K/Akt pathway may contribute to sorafenib resistance in HCC. The mechanisms that underlie the role of Akt activation in this resistance remain unclear
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