Inducing and exploiting vulnerabilities for the treatment of liver cancer
Liver cancer remains difficult to treat, owing to a paucity of drugs that target critical dependencies 1 , 2 ; broad-spectrum kinase inhibitors such as sorafenib provide only a modest benefit to patients with hepatocellular carcinoma 3 . The induction of senescence may represent a strategy for the t...
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| Vydané v: | Nature (London) Ročník 574; číslo 7777; s. 268 - 272 |
|---|---|
| Hlavní autori: | , , , , , , , , , , , , , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | English |
| Vydavateľské údaje: |
London
Nature Publishing Group UK
01.10.2019
Nature Publishing Group |
| Predmet: | |
| ISSN: | 0028-0836, 1476-4687, 1476-4687 |
| On-line prístup: | Získať plný text |
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| Abstract | Liver cancer remains difficult to treat, owing to a paucity of drugs that target critical dependencies
1
,
2
; broad-spectrum kinase inhibitors such as sorafenib provide only a modest benefit to patients with hepatocellular carcinoma
3
. The induction of senescence may represent a strategy for the treatment of cancer, especially when combined with a second drug that selectively eliminates senescent cancer cells (senolysis)
4
,
5
. Here, using a kinome-focused genetic screen, we show that pharmacological inhibition of the DNA-replication kinase CDC7 induces senescence selectively in liver cancer cells with mutations in
TP53
. A follow-up chemical screen identified the antidepressant sertraline as an agent that kills hepatocellular carcinoma cells that have been rendered senescent by inhibition of CDC7. Sertraline suppressed mTOR signalling, and selective drugs that target this pathway were highly effective in causing the apoptotic cell death of hepatocellular carcinoma cells treated with a CDC7 inhibitor. The feedback reactivation of mTOR signalling after its inhibition
6
is blocked in cells that have been treated with a CDC7 inhibitor, which leads to the sustained inhibition of mTOR and cell death. Using multiple in vivo mouse models of liver cancer, we show that treatment with combined inhibition of of CDC7 and mTOR results in a marked reduction of tumour growth. Our data indicate that exploiting an induced vulnerability could be an effective treatment for liver cancer.
CDC7 inhibition selectively induces senescence in hepatocellular carcinoma cells with
TP53
mutations, which enables the selective apoptotic cell death of these senescent cells using inhibitors of mTOR signalling. |
|---|---|
| AbstractList | Liver cancer remains difficult to treat, owing to a paucity of drugs that target critical dependencies
; broad-spectrum kinase inhibitors such as sorafenib provide only a modest benefit to patients with hepatocellular carcinoma
. The induction of senescence may represent a strategy for the treatment of cancer, especially when combined with a second drug that selectively eliminates senescent cancer cells (senolysis)
. Here, using a kinome-focused genetic screen, we show that pharmacological inhibition of the DNA-replication kinase CDC7 induces senescence selectively in liver cancer cells with mutations in TP53. A follow-up chemical screen identified the antidepressant sertraline as an agent that kills hepatocellular carcinoma cells that have been rendered senescent by inhibition of CDC7. Sertraline suppressed mTOR signalling, and selective drugs that target this pathway were highly effective in causing the apoptotic cell death of hepatocellular carcinoma cells treated with a CDC7 inhibitor. The feedback reactivation of mTOR signalling after its inhibition
is blocked in cells that have been treated with a CDC7 inhibitor, which leads to the sustained inhibition of mTOR and cell death. Using multiple in vivo mouse models of liver cancer, we show that treatment with combined inhibition of of CDC7 and mTOR results in a marked reduction of tumour growth. Our data indicate that exploiting an induced vulnerability could be an effective treatment for liver cancer. Liver cancer remains difficult to treat due to a paucity of drugs that target critical dependencies1,2 and broad spectrum kinase inhibitors like sorafenib provide only modest benefit to hepatocellular carcinoma (HCC) patients3. Induction of senescence may represent a promising strategy for the treatment of cancer, especially when such pro-senescence therapy is combined with a second drug that selectively eliminates senescent cancer cells (senolysis)4,5. Through a kinome-focused genetic screen, we report here that pharmacological inhibition of the DNA replication kinase CDC7 induces senescence selectively in TP53 mutant liver cancer cells. A follow-up chemical screen identified the anti-depressant sertraline as an agent that kills HCC cells rendered senescent by CDC7 inhibition. Sertraline supressed mTOR signalling, and selective drugs targeting this pathway were highly effective in causing apoptotic cell death of CDC7 inhibitor-treated HCC cells. Mechanistically, we report that the feedback re-activation of mTOR signalling following its inhibition6 is blocked in CDC7-inhibitor treated cells, leading to sustained mTOR inhibition and cell death. Using multiple in vivo liver cancer models, we show that combination of CDC7 and mTOR inhibitors results in dramatic tumour growth inhibition. More generally, our data indicate that exploiting an induced vulnerability could be an effective treatment of liver cancer. Liver cancer remains difficult to treat, owing to a paucity of drugs that target critical dependencies 1 , 2 ; broad-spectrum kinase inhibitors such as sorafenib provide only a modest benefit to patients with hepatocellular carcinoma 3 . The induction of senescence may represent a strategy for the treatment of cancer, especially when combined with a second drug that selectively eliminates senescent cancer cells (senolysis) 4 , 5 . Here, using a kinome-focused genetic screen, we show that pharmacological inhibition of the DNA-replication kinase CDC7 induces senescence selectively in liver cancer cells with mutations in TP53 . A follow-up chemical screen identified the antidepressant sertraline as an agent that kills hepatocellular carcinoma cells that have been rendered senescent by inhibition of CDC7. Sertraline suppressed mTOR signalling, and selective drugs that target this pathway were highly effective in causing the apoptotic cell death of hepatocellular carcinoma cells treated with a CDC7 inhibitor. The feedback reactivation of mTOR signalling after its inhibition 6 is blocked in cells that have been treated with a CDC7 inhibitor, which leads to the sustained inhibition of mTOR and cell death. Using multiple in vivo mouse models of liver cancer, we show that treatment with combined inhibition of of CDC7 and mTOR results in a marked reduction of tumour growth. Our data indicate that exploiting an induced vulnerability could be an effective treatment for liver cancer. CDC7 inhibition selectively induces senescence in hepatocellular carcinoma cells with TP53 mutations, which enables the selective apoptotic cell death of these senescent cells using inhibitors of mTOR signalling. Liver cancer remains difficult to treat, owing to a paucity of drugs that target critical dependencies.sup.1,2; broad-spectrum kinase inhibitors such as sorafenib provide only a modest benefit to patients with hepatocellular carcinoma.sup.3. The induction of senescence may represent a strategy for the treatment of cancer, especially when combined with a second drug that selectively eliminates senescent cancer cells (senolysis).sup.4,5. Here, using a kinome-focused genetic screen, we show that pharmacological inhibition of the DNA-replication kinase CDC7 induces senescence selectively in liver cancer cells with mutations in TP53. A follow-up chemical screen identified the antidepressant sertraline as an agent that kills hepatocellular carcinoma cells that have been rendered senescent by inhibition of CDC7. Sertraline suppressed mTOR signalling, and selective drugs that target this pathway were highly effective in causing the apoptotic cell death of hepatocellular carcinoma cells treated with a CDC7 inhibitor. The feedback reactivation of mTOR signalling after its inhibition.sup.6 is blocked in cells that have been treated with a CDC7 inhibitor, which leads to the sustained inhibition of mTOR and cell death. Using multiple in vivo mouse models of liver cancer, we show that treatment with combined inhibition of of CDC7 and mTOR results in a marked reduction of tumour growth. Our data indicate that exploiting an induced vulnerability could be an effective treatment for liver cancer. Liver cancer remains difficult to treat, owing to a paucity of drugs that target critical dependencies; broad-spectrum kinase inhibitors such as sorafenib provide only a modest benefit to patients with hepatocellular carcinoma. The induction of senescence may represent a strategy for the treatment of cancer, especially when combined with a second drug that selectively eliminates senescent cancer cells (senolysis). Here, using a kinome-focused genetic screen, we show that pharmacological inhibition of the DNA-replication kinase CDC7 induces senescence selectively in liver cancer cells with mutations in TP53. A follow-up chemical screen identified the antidepressant sertraline as an agent that kills hepatocellular carcinoma cells that have been rendered senescent by inhibition of CDC7. Sertraline suppressed mTOR signalling, and selective drugs that target this pathway were highly effective in causing the apoptotic cell death of hepatocellular carcinoma cells treated with a CDC7 inhibitor. The feedback reactivation of mTOR signalling after its inhibition is blocked in cells that have been treated with a CDC7 inhibitor, which leads to the sustained inhibition of mTOR and cell death. Using multiple in vivo mouse models of liver cancer, we show that treatment with combined inhibition of of CDC7 and mTOR results in a marked reduction of tumour growth. Our data indicate that exploiting an induced vulnerability could be an effective treatment for liver cancer. Liver cancer remains difficult to treat, owing to a paucity of drugs that target critical dependencies.sup.1,2; broad-spectrum kinase inhibitors such as sorafenib provide only a modest benefit to patients with hepatocellular carcinoma.sup.3. The induction of senescence may represent a strategy for the treatment of cancer, especially when combined with a second drug that selectively eliminates senescent cancer cells (senolysis).sup.4,5. Here, using a kinome-focused genetic screen, we show that pharmacological inhibition of the DNA-replication kinase CDC7 induces senescence selectively in liver cancer cells with mutations in TP53. A follow-up chemical screen identified the antidepressant sertraline as an agent that kills hepatocellular carcinoma cells that have been rendered senescent by inhibition of CDC7. Sertraline suppressed mTOR signalling, and selective drugs that target this pathway were highly effective in causing the apoptotic cell death of hepatocellular carcinoma cells treated with a CDC7 inhibitor. The feedback reactivation of mTOR signalling after its inhibition.sup.6 is blocked in cells that have been treated with a CDC7 inhibitor, which leads to the sustained inhibition of mTOR and cell death. Using multiple in vivo mouse models of liver cancer, we show that treatment with combined inhibition of of CDC7 and mTOR results in a marked reduction of tumour growth. Our data indicate that exploiting an induced vulnerability could be an effective treatment for liver cancer. CDC7 inhibition selectively induces senescence in hepatocellular carcinoma cells with TP53 mutations, which enables the selective apoptotic cell death of these senescent cells using inhibitors of mTOR signalling. Liver cancer remains difficult to treat, owing to a paucity of drugs that target critical dependencies1,2; broad-spectrum kinase inhibitors such as sorafenib provide only a modest benefit to patients with hepatocellular carcinoma3. The induction of senescence may represent a strategy for the treatment of cancer, especially when combined with a second drug that selectively eliminates senescent cancer cells (senolysis)4,5. Here, using a kinome-focused genetic screen, we show that pharmacological inhibition of the DNA-replication kinase CDC7 induces senescence selectively in liver cancer cells with mutations in TP53. A follow-up chemical screen identified the antidepressant sertraline as an agent that kills hepatocellular carcinoma cells that have been rendered senescent by inhibition of CDC7. Sertraline suppressed mTOR signalling, and selective drugs that target this pathway were highly effective in causing the apoptotic cell death of hepatocellular carcinoma cells treated with a CDC7 inhibitor. The feedback reactivation of mTOR signalling after its inhibition6 is blocked in cells that have been treated with a CDC7 inhibitor, which leads to the sustained inhibition of mTOR and cell death. Using multiple in vivo mouse models of liver cancer, we show that treatment with combined inhibition of of CDC7 and mTOR results in a marked reduction of tumour growth. Our data indicate that exploiting an induced vulnerability could be an effective treatment for liver cancer.Liver cancer remains difficult to treat, owing to a paucity of drugs that target critical dependencies1,2; broad-spectrum kinase inhibitors such as sorafenib provide only a modest benefit to patients with hepatocellular carcinoma3. The induction of senescence may represent a strategy for the treatment of cancer, especially when combined with a second drug that selectively eliminates senescent cancer cells (senolysis)4,5. Here, using a kinome-focused genetic screen, we show that pharmacological inhibition of the DNA-replication kinase CDC7 induces senescence selectively in liver cancer cells with mutations in TP53. A follow-up chemical screen identified the antidepressant sertraline as an agent that kills hepatocellular carcinoma cells that have been rendered senescent by inhibition of CDC7. Sertraline suppressed mTOR signalling, and selective drugs that target this pathway were highly effective in causing the apoptotic cell death of hepatocellular carcinoma cells treated with a CDC7 inhibitor. The feedback reactivation of mTOR signalling after its inhibition6 is blocked in cells that have been treated with a CDC7 inhibitor, which leads to the sustained inhibition of mTOR and cell death. Using multiple in vivo mouse models of liver cancer, we show that treatment with combined inhibition of of CDC7 and mTOR results in a marked reduction of tumour growth. Our data indicate that exploiting an induced vulnerability could be an effective treatment for liver cancer. |
| Audience | Academic |
| Author | Sanchez, Antonio Mulero Jochems, Fleur Morris, Ben Beijersbergen, Roderick L. Wang, Wei Vegna, Serena de Oliveira, Rodrigo Leite Mainardi, Sara Bernards, René Qin, Wenxin Gao, Dongmei Wang, Cun Xue, Zheng Evers, Bastiaan Lieftink, Cor du Chatinier, Aimée Benedict, Bente Gadiot, Jules Jin, Guangzhi Akkari, Leila Jin, Haojie Wang, Liqin te Riele, Hein Ramirez, Christel Schepers, Arnout |
| AuthorAffiliation | 2 Division of Molecular Carcinogenesis, Oncode Institute. The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands 1 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China 6 Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China 3 Division of Tumour Biology and Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands 4 Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands 5 Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China |
| AuthorAffiliation_xml | – name: 5 Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China – name: 6 Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China – name: 2 Division of Molecular Carcinogenesis, Oncode Institute. The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands – name: 3 Division of Tumour Biology and Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands – name: 1 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China – name: 4 Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands |
| Author_xml | – sequence: 1 givenname: Cun surname: Wang fullname: Wang, Cun organization: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Oncode Institute, Division of Molecular Carcinogenesis, The Netherlands Cancer Institute – sequence: 2 givenname: Serena surname: Vegna fullname: Vegna, Serena organization: Oncode Institute, Division of Tumour Biology and Immunology, The Netherlands Cancer Institute – sequence: 3 givenname: Haojie surname: Jin fullname: Jin, Haojie organization: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Oncode Institute, Division of Molecular Carcinogenesis, The Netherlands Cancer Institute – sequence: 4 givenname: Bente surname: Benedict fullname: Benedict, Bente organization: Oncode Institute, Division of Tumour Biology and Immunology, The Netherlands Cancer Institute – sequence: 5 givenname: Cor surname: Lieftink fullname: Lieftink, Cor organization: Oncode Institute, Division of Molecular Carcinogenesis, The Netherlands Cancer Institute – sequence: 6 givenname: Christel surname: Ramirez fullname: Ramirez, Christel organization: Oncode Institute, Division of Tumour Biology and Immunology, The Netherlands Cancer Institute – sequence: 7 givenname: Rodrigo Leite surname: de Oliveira fullname: de Oliveira, Rodrigo Leite organization: Oncode Institute, Division of Molecular Carcinogenesis, The Netherlands Cancer Institute – sequence: 8 givenname: Ben surname: Morris fullname: Morris, Ben organization: Oncode Institute, Division of Molecular Carcinogenesis, The Netherlands Cancer Institute – sequence: 9 givenname: Jules surname: Gadiot fullname: Gadiot, Jules organization: Oncode Institute, Division of Tumour Biology and Immunology, The Netherlands Cancer Institute – sequence: 10 givenname: Wei surname: Wang fullname: Wang, Wei organization: Division of Cell Biology, The Netherlands Cancer Institute – sequence: 11 givenname: Aimée surname: du Chatinier fullname: du Chatinier, Aimée organization: Oncode Institute, Division of Molecular Carcinogenesis, The Netherlands Cancer Institute – sequence: 12 givenname: Liqin surname: Wang fullname: Wang, Liqin organization: Oncode Institute, Division of Molecular Carcinogenesis, The Netherlands Cancer Institute – sequence: 13 givenname: Dongmei surname: Gao fullname: Gao, Dongmei organization: Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education – sequence: 14 givenname: Bastiaan surname: Evers fullname: Evers, Bastiaan organization: Oncode Institute, Division of Molecular Carcinogenesis, The Netherlands Cancer Institute – sequence: 15 givenname: Guangzhi surname: Jin fullname: Jin, Guangzhi organization: Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University – sequence: 16 givenname: Zheng surname: Xue fullname: Xue, Zheng organization: Oncode Institute, Division of Molecular Carcinogenesis, The Netherlands Cancer Institute – sequence: 17 givenname: Arnout surname: Schepers fullname: Schepers, Arnout organization: Oncode Institute, Division of Molecular Carcinogenesis, The Netherlands Cancer Institute – sequence: 18 givenname: Fleur surname: Jochems fullname: Jochems, Fleur organization: Oncode Institute, Division of Molecular Carcinogenesis, The Netherlands Cancer Institute – sequence: 19 givenname: Antonio Mulero surname: Sanchez fullname: Sanchez, Antonio Mulero organization: Oncode Institute, Division of Molecular Carcinogenesis, The Netherlands Cancer Institute – sequence: 20 givenname: Sara surname: Mainardi fullname: Mainardi, Sara organization: Oncode Institute, Division of Molecular Carcinogenesis, The Netherlands Cancer Institute – sequence: 21 givenname: Hein surname: te Riele fullname: te Riele, Hein organization: Oncode Institute, Division of Tumour Biology and Immunology, The Netherlands Cancer Institute – sequence: 22 givenname: Roderick L. surname: Beijersbergen fullname: Beijersbergen, Roderick L. organization: Oncode Institute, Division of Molecular Carcinogenesis, The Netherlands Cancer Institute – sequence: 23 givenname: Wenxin surname: Qin fullname: Qin, Wenxin email: wxqin@sjtu.edu.cn organization: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine – sequence: 24 givenname: Leila surname: Akkari fullname: Akkari, Leila email: l.akkari@nki.nl organization: Oncode Institute, Division of Tumour Biology and Immunology, The Netherlands Cancer Institute – sequence: 25 givenname: René surname: Bernards fullname: Bernards, René email: r.bernards@nki.nl organization: Oncode Institute, Division of Molecular Carcinogenesis, The Netherlands Cancer Institute |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/31578521$$D View this record in MEDLINE/PubMed |
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; broad-spectrum kinase inhibitors such as... Liver cancer remains difficult to treat, owing to a paucity of drugs that target critical dependencies ; broad-spectrum kinase inhibitors such as sorafenib... Liver cancer remains difficult to treat, owing to a paucity of drugs that target critical dependencies.sup.1,2; broad-spectrum kinase inhibitors such as... Liver cancer remains difficult to treat, owing to a paucity of drugs that target critical dependencies; broad-spectrum kinase inhibitors such as sorafenib... Liver cancer remains difficult to treat, owing to a paucity of drugs that target critical dependencies1,2; broad-spectrum kinase inhibitors such as sorafenib... Liver cancer remains difficult to treat due to a paucity of drugs that target critical dependencies1,2 and broad spectrum kinase inhibitors like sorafenib... |
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| Title | Inducing and exploiting vulnerabilities for the treatment of liver cancer |
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