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Dual Inhibition of mTOR in hepatocellular carcinoma induces tumor regression, return to normal liver gene expression and autophagy

Elnakat Thomas, Hala, Mercer, Carol A., Carnevalli, Larissa S., Park, Jongsun, Andersen, Jesper B., Conner, Elizabeth A., Tanaka, Kazuhiro, Matsutani, Tomoo, Iwanami, Akio, Aronow, Bruce J., Liu, Manway, Thorgeisson, Snorri S., Mischel, Paul S., Thomas, George and Kozma, Sara C. (2012) Dual Inhibition of mTOR in hepatocellular carcinoma induces tumor regression, return to normal liver gene expression and autophagy. Science Translational Medicine, 4 (139). ra84. ISSN 1946-6234


Hepatocellular carcinoma (HCC) affects more than half a million people worldwide and is the third most common cause of cancer deaths. Given the need for novel therapies and that 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 proliferation of cultured HCC cells, which closely paralleled 4E-BP1 dephosphorylation. In a mouse model approximating human HCC with poor prognosis, the two drugs in combination, but not as single agents, induced a dramatic regression in tumor development.
However, BEZ235 was almost as effective as the combination in inhibiting 4E-BP1 phosphorylation. Importantly, microarray analyses revealed a large and unique number of genes reverting to normal liver tissue expression levels in tumors
treated with both drugs, but not with either drug alone. These analyses also revealed the down regulation of a number of autophagy genes in tumors compared to normal liver. This observation led to the finding that the drug combination has a profound effect on ULK1 phosphorylation and autophagy in
culture and in parallel induces mitophagy in tumors, a process which acts as a tumor suppressor in liver. As drug synergy is achieved at low doses of both drugs, this may also decrease potential toxicity, while increasing target specificity. These observations have led to an investigator initiated Phase 1B-2 dose escalation trial with RAD001 combined with BEZ235 in patients with advanced solid tumors, including HCC.

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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14