mTOR inhibitors synergize on regression, reversal of gene expression, and autophagy in hepatocellular carcinoma

Hala Elnakat Thomas, Carol A. Mercer, Larissa S. Carnevalli, Jongsun Park, Jesper B. Andersen, Elizabeth A. Conner, Kazuhiro Tanaka, Tomoo Matsutani, Akio Iwanami, Bruce J. Aronow, Liu Manway, S. Michel Maira, Snorri S. Thorgeirsson, Paul S. Mischel, George Thomas, Sara C. Kozma

Research output: Contribution to journalArticle

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Abstract

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 up-regulated in 50% of HCCs, we compared the effects of the U.S. Food and Drug Administration-approved mTOR-allosteric inhibitor, RAD001, with a new-generation phosphatidylinositol 3-kinase/mTOR adenosine triphosphate-site competitive inhibitor, BEZ235. Unexpectedly, the two drugs acted synergistically in inhibiting the proliferation of cultured HCC cells. The synergistic effect closely paralleled eukaryotic initiation factor 4E-binding protein 1 (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 marked regression in tumor burden. However, in the tumor, BEZ235 alone was as effective as the combination in inhibiting 4E-BP1 phosphorylation, which suggests that 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.

Original languageEnglish
Article number139ra84
JournalScience Translational Medicine
Volume4
Issue number139
DOIs
Publication statusPublished - 2012 Jun 20
Externally publishedYes

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Autophagy
Sirolimus
Hepatocellular Carcinoma
Gene Expression
Neoplasms
Carrier Proteins
Drug Combinations
Liver
Mitochondrial Degradation
Eukaryotic Initiation Factor-4E
Phosphatidylinositol 3-Kinase
Pharmaceutical Preparations
United States Food and Drug Administration
Microarray Analysis
Tumor Burden
Genes
Cause of Death
Phosphotransferases
Down-Regulation
Adenosine Triphosphate

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Thomas, H. E., Mercer, C. A., Carnevalli, L. S., Park, J., Andersen, J. B., Conner, E. A., ... Kozma, S. C. (2012). mTOR inhibitors synergize on regression, reversal of gene expression, and autophagy in hepatocellular carcinoma. Science Translational Medicine, 4(139), [139ra84]. https://doi.org/10.1126/scitranslmed.3003923

mTOR inhibitors synergize on regression, reversal of gene expression, and autophagy in hepatocellular carcinoma. / Thomas, Hala Elnakat; Mercer, Carol A.; Carnevalli, Larissa S.; Park, Jongsun; Andersen, Jesper B.; Conner, Elizabeth A.; Tanaka, Kazuhiro; Matsutani, Tomoo; Iwanami, Akio; Aronow, Bruce J.; Manway, Liu; Maira, S. Michel; Thorgeirsson, Snorri S.; Mischel, Paul S.; Thomas, George; Kozma, Sara C.

In: Science Translational Medicine, Vol. 4, No. 139, 139ra84, 20.06.2012.

Research output: Contribution to journalArticle

Thomas, HE, Mercer, CA, Carnevalli, LS, Park, J, Andersen, JB, Conner, EA, Tanaka, K, Matsutani, T, Iwanami, A, Aronow, BJ, Manway, L, Maira, SM, Thorgeirsson, SS, Mischel, PS, Thomas, G & Kozma, SC 2012, 'mTOR inhibitors synergize on regression, reversal of gene expression, and autophagy in hepatocellular carcinoma', Science Translational Medicine, vol. 4, no. 139, 139ra84. https://doi.org/10.1126/scitranslmed.3003923
Thomas, Hala Elnakat ; Mercer, Carol A. ; Carnevalli, Larissa S. ; Park, Jongsun ; Andersen, Jesper B. ; Conner, Elizabeth A. ; Tanaka, Kazuhiro ; Matsutani, Tomoo ; Iwanami, Akio ; Aronow, Bruce J. ; Manway, Liu ; Maira, S. Michel ; Thorgeirsson, Snorri S. ; Mischel, Paul S. ; Thomas, George ; Kozma, Sara C. / mTOR inhibitors synergize on regression, reversal of gene expression, and autophagy in hepatocellular carcinoma. In: Science Translational Medicine. 2012 ; Vol. 4, No. 139.
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AU - Tanaka, Kazuhiro

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AU - Maira, S. Michel

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