Abstract
Allosteric and ATP-site mTOR inhibitors act synergistically to induce tumor regression.
Major finding: Allosteric and ATP-site mTOR inhibitors act synergistically to induce tumor regression.
Mechanism: Synergistic mTOR inhibition restores normal gene expression patterns and induces autophagy.
Impact: A phase IB–II trial of BEZ235 plus everolimus has been initiated for solid tumors including HCC.
Few treatment options are available for hepatocellular carcinoma (HCC), one of the most common and lethal cancers worldwide. Because upregulation of the mTOR pathway has been observed in approximately half of HCCs, Thomas and colleagues evaluated the efficacy of 2 mTOR inhibitors, everolimus and BEZ235, in HCC. Everolimus is a derivative of rapamycin that inhibits mTOR complex 1 (mTORC1) signaling by binding to an allosteric site near the mTOR kinase domain. Everolimus does not inhibit mTOR complex 2 (mTORC2), and ultimately leads to phosphoinositide 3-kinase activation through inhibition of mTORC1-mediated negative feedback. In contrast, ATP-competitive mTOR inhibitors, such as BEZ235, bind to the mTOR active site and inhibit both mTORC1 and mTORC2 kinase activity. Surprisingly, even though they both target mTOR, low doses of everolimus and BEZ235 acted synergistically in vitro to inhibit cell proliferation and phosphorylation of mTOR targets more effectively than either drug alone. Moreover, in a diethylnitrosamine (DEN)-induced mouse model resembling human HCC with poor prognosis, combined treatment with low doses of everolimus and BEZ235 led to increased tumor regression relative to higher doses of either drug alone. Gene expression analysis revealed that the combination of everolimus and BEZ235 in DEN-induced tumors reverted the expression of 475 genes back to normal liver expression levels, whereas 354 of those genes were not reverted by single-drug treatment. Everolimus and BEZ235 also acted synergistically to induce autophagy both in vitro and in DEN-induced tumors. Together, these data suggest that combined use of mTOR inhibitors may be more effective in patients with HCC and other advanced solid tumors and have thus led to an investigator-initiated phase IB dose-escalation study and phase II clinical trial of BEZ235 in combination with everolimus.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
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