Research ArticleHepatocellular carcinoma

mTOR Inhibitors Synergize on Regression, Reversal of Gene Expression, and Autophagy in Hepatocellular Carcinoma

Science Translational Medicine  20 Jun 2012:
Vol. 4, Issue 139, pp. 139ra84
DOI: 10.1126/scitranslmed.3003923

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Bridging the Generation Gap

Kids of every generation disdain their elders—who clearly don’t understand them and are stuck in the past. Newer is better, after all. But sometimes, a blend of the old and new may be exactly what’s needed to solve a particular problem. Thomas et al. set out to see whether the new—the phosphatidylinositol 3-kinase/mammalian target of rapamycin (mTOR) adenosine triphosphate–site competitive inhibitor BEZ235—was better than the old—the U.S. Food and Drug Administration–approved mTOR-allosteric inhibitor RAD001. What they instead found was that these two drugs worked together to treat hepatocellular carcinoma (HCC).

mTOR signaling is up-regulated in about 50% of HCCs. When the authors tested two mTOR-targeting drugs, BEZ235 and RAD001, on cultured HCC cells, they unexpectedly found that the drugs acted synergistically. In a mouse model that mimics human HCC, the two drugs induced a marked regression in tumor burden through a mechanism that involved down-regulation of genes involved in autophagy—where the cell degrades its own components. In patients with HCC, dysregulation of autophagy genes correlated with poor prognosis. The authors are now taking this observation into clinical trials to determine whether it holds true in people. By working together, old and new mTOR inhibitors may provide a new therapeutic option for HCC.