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 Bøje 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

doi:10.1126/scitranslmed.3003923

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 Bøje 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

74 Citations (Scopus)

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 language	English
Journal	Science Translational Medicine
Volume	4
Issue number	139
Pages (from-to)	139ra84
DOIs	https://doi.org/10.1126/scitranslmed.3003923
Publication status	Published - 20 Jun 2012
Externally published	Yes

Keywords

Animals
Antineoplastic Agents
Autophagy
Carcinoma, Hepatocellular
Humans
Imidazoles
Immunoblotting
Liver Neoplasms
Male
Mice
Mice, Inbred C57BL
Protein-Serine-Threonine Kinases
Quinolines
Sirolimus
TOR Serine-Threonine Kinases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1126/scitranslmed.3003923

Cite this

Thomas, H. E., Mercer, C. A., Carnevalli, L. S., Park, J., Andersen, J. B., Conner, E. A., Tanaka, K., Matsutani, T., Iwanami, A., Aronow, B. J., Manway, L., Maira, S. M., Thorgeirsson, S. S., Mischel, P. S., Thomas, G., & 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

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, pp. 139ra84. https://doi.org/10.1126/scitranslmed.3003923

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

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.",

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author = "Thomas, {Hala Elnakat} and Mercer, {Carol A} and Carnevalli, {Larissa S} and Jongsun Park and Andersen, {Jesper B{\o}je} and Conner, {Elizabeth A} and Kazuhiro Tanaka and Tomoo Matsutani and Akio Iwanami and Aronow, {Bruce J} and Liu Manway and Maira, {S Michel} and Thorgeirsson, {Snorri S} and Mischel, {Paul S} and George Thomas and Kozma, {Sara C}",

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pages = "139ra84",

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TY - JOUR

T1 - mTOR inhibitors synergize on regression, reversal of gene expression, and autophagy in hepatocellular carcinoma

AU - Thomas, Hala Elnakat

AU - Mercer, Carol A

AU - Carnevalli, Larissa S

AU - Park, Jongsun

AU - Andersen, Jesper Bøje

AU - Conner, Elizabeth A

AU - Tanaka, Kazuhiro

AU - Matsutani, Tomoo

AU - Iwanami, Akio

AU - Aronow, Bruce J

AU - Manway, Liu

AU - Maira, S Michel

AU - Thorgeirsson, Snorri S

AU - Mischel, Paul S

AU - Thomas, George

AU - Kozma, Sara C

PY - 2012/6/20

Y1 - 2012/6/20

N2 - 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.

AB - 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.

KW - Animals

KW - Antineoplastic Agents

KW - Autophagy

KW - Carcinoma, Hepatocellular

KW - Humans

KW - Imidazoles

KW - Immunoblotting

KW - Liver Neoplasms

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Protein-Serine-Threonine Kinases

KW - Quinolines

KW - Sirolimus

KW - TOR Serine-Threonine Kinases

U2 - 10.1126/scitranslmed.3003923

DO - 10.1126/scitranslmed.3003923

M3 - Journal article

C2 - 22539746

SN - 1946-6234

VL - 4

SP - 139ra84

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 139

ER -

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

Abstract

Keywords

UN SDGs

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