mTOR Inhibitors Synergize Regression, Reversal of Gene Expression, and Autophagy in Hepatocellular Carcinoma
Menée sur des lignées cellulaires et à l'aide d'un modèle murin de carcinome hépatocellulaire, cette étude évalue les effets antitumoraux de deux inhibiteurs de la voie mTOR, seuls ou en combinaison
Hepatocellular carcinoma (HCC) affects more than half a million people worldwide and is the third most common cause of cancer deaths. Because mammalian Target of Rapamycin (mTOR)-signaling is upregulated in 50% of HCCs, we compared the effects of the FDA-approved mTOR-allosteric inhibitor, RAD001, with a new generation PI3K/mTOR ATP-site competitive inhibitor, BEZ235. Unexpectedly, the two drugs acted synergistically in inhibiting the proliferation of cultured HCC cells. The synergistic effect closely paralleled 4E-BP1 dephosphorylation, which is implicated in the suppression of tumor cell proliferation. In a mouse model approximating human HCC, the drugs in combination, but not singly, induced a dramatic regression in tumor burden. However in the tumor, BEZ235 alone was as effective as the combination in inhibiting 4E-BP1 phosphorylation, which suggest additional target(s) may also be involved. Microarray analyses revealed a large number of genes that reverted to normal liver tissue expression in mice treated with both drugs, but not either drug alone. These analyses also revealed the down regulation of autophagy genes in tumors compared to normal liver. Moreover, in HCC patients, altered expression of autophagy genes was associated with poor prognosis. Consistent with these findings, the drug combination had a profound effect on UNC51-like kinase 1 (ULK1) dephosphorylation and autophagy in culture, independent of 4E-BP1, and in parallel induced tumor mitophagy, a tumor-suppressor process in liver. These observations have led to an investigator-initiated Phase 1B-2 dose escalation trial with RAD001 combined with BEZ235 in patients with HCC and other advanced solid tumors.