Ibrutinib potentiates anti-hepatocarcinogenic efficacy of sorafenib by targeting EGFR in tumor cells and BTK in immune cells in the stroma
Hepatocellular carcinoma (HCC), the most prevalent primary liver cancer, is a leading cause of cancer-related death worldwide because of rising incidence and limited therapy. Although treatment with sorafenib or lenvatinib is the standard of care in advanced-stage HCC patients, the survival benefit...
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Published in | Molecular cancer therapeutics Vol. 19; no. 2; pp. 384 - 396 |
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Main Authors | , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
03.10.2019
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Online Access | Get full text |
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Abstract | Hepatocellular carcinoma (HCC), the most prevalent primary liver cancer, is a leading cause of cancer-related death worldwide because of rising incidence and limited therapy. Although treatment with sorafenib or lenvatinib is the standard of care in advanced-stage HCC patients, the survival benefit from sorafenib is limited due to low response rate and drug resistance. Ibrutinib, an irreversible tyrosine kinase inhibitor (TKI) of TEC (e.g. BTK) and ErbB (e.g. EGFR) families, is an approved treatment for B cell malignancies. Here, we demonstrate that ibrutinib inhibits proliferation, spheroid formation and clonogenic survival of HCC cells including sorafenib resistant cells. Mechanistically, ibrutinib inactivated EGFR and its downstream Akt and ERK signaling in HCC cells, and downregulated a set of critical genes involved in cell proliferation, migration, survival and stemness, and upregulated genes promoting differentiation. Moreover, ibrutinib showed synergy with sorafenib or regorafenib, a sorafenib congener by inducing apoptosis of HCC cells. In vivo, this TKI combination significantly inhibited HCC growth and prolonged survival of immune-deficient mice bearing human HCCLM3 xenograft tumors and immune competent mice bearing orthotopic mouse Hepa tumors at a dose that did not exhibit systemic toxicity. In immune competent mice, the ibrutinib-sorafenib combination reduced the numbers of BTK+ immune cells in the tumor microenvironment. Importantly, we found that the BTK+ immune cells were also enriched in the tumor microenvironment in a subset of primary human HCCs. Collectively, our findings implicate BTK signaling in hepatocarcinogenesis and support clinical trials of the sorafenib-ibrutinib combination for this deadly disease. |
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AbstractList | Hepatocellular carcinoma (HCC), the most prevalent primary liver cancer, is a leading cause of cancer-related death worldwide because of rising incidence and limited therapy. Although treatment with sorafenib or lenvatinib is the standard of care in advanced-stage HCC patients, the survival benefit from sorafenib is limited due to low response rate and drug resistance. Ibrutinib, an irreversible tyrosine kinase inhibitor (TKI) of TEC (e.g. BTK) and ErbB (e.g. EGFR) families, is an approved treatment for B cell malignancies. Here, we demonstrate that ibrutinib inhibits proliferation, spheroid formation and clonogenic survival of HCC cells including sorafenib resistant cells. Mechanistically, ibrutinib inactivated EGFR and its downstream Akt and ERK signaling in HCC cells, and downregulated a set of critical genes involved in cell proliferation, migration, survival and stemness, and upregulated genes promoting differentiation. Moreover, ibrutinib showed synergy with sorafenib or regorafenib, a sorafenib congener by inducing apoptosis of HCC cells. In vivo, this TKI combination significantly inhibited HCC growth and prolonged survival of immune-deficient mice bearing human HCCLM3 xenograft tumors and immune competent mice bearing orthotopic mouse Hepa tumors at a dose that did not exhibit systemic toxicity. In immune competent mice, the ibrutinib-sorafenib combination reduced the numbers of BTK+ immune cells in the tumor microenvironment. Importantly, we found that the BTK+ immune cells were also enriched in the tumor microenvironment in a subset of primary human HCCs. Collectively, our findings implicate BTK signaling in hepatocarcinogenesis and support clinical trials of the sorafenib-ibrutinib combination for this deadly disease. |
Author | Jacob, Samson T. Lin, Cho-Hao Wani, Nissar A. Hu, Peng Barajas, Juan M. Yu, Lianbo Zhang, Xiaoli Ghoshal, Kalpana Elkholy, Khadija H. Li, Ding Noonan, Anne M. Khan, Wasif N. Bai, Xue-Feng |
AuthorAffiliation | 2 Comprehensive Cancer Center, The Ohio State University, Columbus, OH 6 Department of Microbiology & Immunology and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 4 Department of Biomedical Informatics, The Ohio State University, Columbus, OH 1 Department of Pathology, The Ohio State University, Columbus, OH 5 Department of Internal Medicine, The Ohio State University, Columbus, OH 3 Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH |
AuthorAffiliation_xml | – name: 5 Department of Internal Medicine, The Ohio State University, Columbus, OH – name: 3 Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH – name: 1 Department of Pathology, The Ohio State University, Columbus, OH – name: 6 Department of Microbiology & Immunology and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL – name: 2 Comprehensive Cancer Center, The Ohio State University, Columbus, OH – name: 4 Department of Biomedical Informatics, The Ohio State University, Columbus, OH |
Author_xml | – sequence: 1 givenname: Cho-Hao surname: Lin fullname: Lin, Cho-Hao organization: Department of Pathology, The Ohio State University, Columbus, OH Comprehensive Cancer Center, The Ohio State University, Columbus, OH Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH Department of Biomedical Informatics, The Ohio State University, Columbus, OH Department of Internal Medicine, The Ohio State University, Columbus, OH Department of Microbiology & Immunology and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL – sequence: 2 givenname: Khadija H. surname: Elkholy fullname: Elkholy, Khadija H. organization: Department of Pathology, The Ohio State University, Columbus, OH Comprehensive Cancer Center, The Ohio State University, Columbus, OH Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH Department of Biomedical Informatics, The Ohio State University, Columbus, OH Department of Internal Medicine, The Ohio State University, Columbus, OH Department of Microbiology & Immunology and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL – sequence: 3 givenname: Nissar A. surname: Wani fullname: Wani, Nissar A. organization: Department of Pathology, The Ohio State University, Columbus, OH Comprehensive Cancer Center, The Ohio State University, Columbus, OH Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH Department of Biomedical Informatics, The Ohio State University, Columbus, OH Department of Internal Medicine, The Ohio State University, Columbus, OH Department of Microbiology & Immunology and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL – sequence: 4 givenname: Ding surname: Li fullname: Li, Ding organization: Department of Pathology, The Ohio State University, Columbus, OH Comprehensive Cancer Center, The Ohio State University, Columbus, OH Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH Department of Biomedical Informatics, The Ohio State University, Columbus, OH Department of Internal Medicine, The Ohio State University, Columbus, OH Department of Microbiology & Immunology and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL – sequence: 5 givenname: Peng surname: Hu fullname: Hu, Peng organization: Department of Pathology, The Ohio State University, Columbus, OH Comprehensive Cancer Center, The Ohio State University, Columbus, OH Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH Department of Biomedical Informatics, The Ohio State University, Columbus, OH Department of Internal Medicine, The Ohio State University, Columbus, OH Department of Microbiology & Immunology and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL – sequence: 6 givenname: Juan M. surname: Barajas fullname: Barajas, Juan M. organization: Department of Pathology, The Ohio State University, Columbus, OH Comprehensive Cancer Center, The Ohio State University, Columbus, OH Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH Department of Biomedical Informatics, The Ohio State University, Columbus, OH Department of Internal Medicine, The Ohio State University, Columbus, OH Department of Microbiology & Immunology and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL – sequence: 7 givenname: Lianbo surname: Yu fullname: Yu, Lianbo organization: Department of Pathology, The Ohio State University, Columbus, OH Comprehensive Cancer Center, The Ohio State University, Columbus, OH Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH Department of Biomedical Informatics, The Ohio State University, Columbus, OH Department of Internal Medicine, The Ohio State University, Columbus, OH Department of Microbiology & Immunology and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL – sequence: 8 givenname: Xiaoli surname: Zhang fullname: Zhang, Xiaoli organization: Department of Pathology, The Ohio State University, Columbus, OH Comprehensive Cancer Center, The Ohio State University, Columbus, OH Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH Department of Biomedical Informatics, The Ohio State University, Columbus, OH Department of Internal Medicine, The Ohio State University, Columbus, OH Department of Microbiology & Immunology and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL – sequence: 9 givenname: Samson T. surname: Jacob fullname: Jacob, Samson T. organization: Department of Pathology, The Ohio State University, Columbus, OH Comprehensive Cancer Center, The Ohio State University, Columbus, OH Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH Department of Biomedical Informatics, The Ohio State University, Columbus, OH Department of Internal Medicine, The Ohio State University, Columbus, OH Department of Microbiology & Immunology and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL – sequence: 10 givenname: Wasif N. surname: Khan fullname: Khan, Wasif N. organization: Department of Pathology, The Ohio State University, Columbus, OH Comprehensive Cancer Center, The Ohio State University, Columbus, OH Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH Department of Biomedical Informatics, The Ohio State University, Columbus, OH Department of Internal Medicine, The Ohio State University, Columbus, OH Department of Microbiology & Immunology and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL – sequence: 11 givenname: Xue-Feng surname: Bai fullname: Bai, Xue-Feng organization: Department of Pathology, The Ohio State University, Columbus, OH Comprehensive Cancer Center, The Ohio State University, Columbus, OH Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH Department of Biomedical Informatics, The Ohio State University, Columbus, OH Department of Internal Medicine, The Ohio State University, Columbus, OH Department of Microbiology & Immunology and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL – sequence: 12 givenname: Anne M. surname: Noonan fullname: Noonan, Anne M. organization: Department of Pathology, The Ohio State University, Columbus, OH Comprehensive Cancer Center, The Ohio State University, Columbus, OH Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH Department of Biomedical Informatics, The Ohio State University, Columbus, OH Department of Internal Medicine, The Ohio State University, Columbus, OH Department of Microbiology & Immunology and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL – sequence: 13 givenname: Kalpana surname: Ghoshal fullname: Ghoshal, Kalpana email: kalpana.ghoshal@osumc.edu organization: Department of Pathology, The Ohio State University, Columbus, OH Comprehensive Cancer Center, The Ohio State University, Columbus, OH Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH Department of Biomedical Informatics, The Ohio State University, Columbus, OH Department of Internal Medicine, The Ohio State University, Columbus, OH Department of Microbiology & Immunology and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL |
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Notes | Authors’ contribution K.G. conceived the project; C.H L., K.E. and K.G. wrote the paper; C.H.L., N.W., K.E. and K.G. designed experiments; C.H.L., N.W., K.E., D.L. and P.H. performed experiments, C.H.L., N.W., K.E., P.H., D.L., Y.L., X.Z., J.M.B., X.B. and W.N.K. analyzed data, C.H.L. generated the figures and A.N., X.B. and W.N.K. edited the paper. |
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Title | Ibrutinib potentiates anti-hepatocarcinogenic efficacy of sorafenib by targeting EGFR in tumor cells and BTK in immune cells in the stroma |
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