AKT Hyperactivation and the Potential of AKT-Targeted Therapy in Diffuse Large B-Cell Lymphoma
AKT signaling is important for proliferation and survival of tumor cells. The clinical significance of AKT activation in diffuse large B-cell lymphoma (DLBCL) is not well analyzed. Here, we assessed expression of phosphorylated AKT (p-AKT) in 522 DLBCL patients. We found that high levels of p-AKT nu...
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| Published in | The American journal of pathology Vol. 187; no. 8; pp. 1700 - 1716 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Elsevier Inc
01.08.2017
American Society for Investigative Pathology |
| Subjects | |
| Online Access | Get full text |
| ISSN | 0002-9440 1525-2191 1525-2191 |
| DOI | 10.1016/j.ajpath.2017.04.009 |
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| Abstract | AKT signaling is important for proliferation and survival of tumor cells. The clinical significance of AKT activation in diffuse large B-cell lymphoma (DLBCL) is not well analyzed. Here, we assessed expression of phosphorylated AKT (p-AKT) in 522 DLBCL patients. We found that high levels of p-AKT nuclear expression, observed in 24.3% of the study cohort, were associated with significantly worse progression-free survival and Myc and Bcl-2 overexpression. However, multivariate analysis indicated that AKT hyperactivation was not an independent factor. miRNA profiling analysis demonstrated that 63 miRNAs directly or indirectly related to the phosphatidylinositol 3-kinase/AKT/mechanistic target of rapamycin pathway were differentially expressed between DLBCLs with high and low p-AKT nuclear expression. We further targeted AKT signaling using a highly selective AKT inhibitor MK-2206 in 26 representative DLBCL cell lines and delineated signaling alterations using a reverse-phase protein array. MK-2206 treatment inhibited lymphoma cell viability, and MK-2206 sensitivity correlated with AKT activation status in DLBCL cells. On MK-2206 treatment, p-AKT levels and downstream targets of AKT signaling were significantly decreased, likely because of the decreased feedback repression; Rictor and phosphatidylinositol 3-kinase expression and other compensatory pathways were also induced. This study demonstrates the clinical and therapeutic implications of AKT hyperactivation in DLBCL and suggests that AKT inhibitors need to be combined with other targeted agents for DLBCL to achieve optimal clinical efficacy. |
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| AbstractList | AKT signaling is important for proliferation and survival of tumor cells. The clinical significance of AKT activation in diffuse large B-cell lymphoma (DLBCL) is not well analyzed. Here, we assessed expression of phosphorylated AKT (p-AKT) in 522 DLBCL patients. We found that high levels of p-AKT nuclear expression, observed in 24.3% of the study cohort, were associated with significantly worse progression-free survival and Myc and Bcl-2 overexpression. However, multivariate analysis indicated that AKT hyperactivation was not an independent factor. miRNA profiling analysis demonstrated that 63 miRNAs directly or indirectly related to the phosphatidylinositol 3-kinase/AKT/mechanistic target of rapamycin pathway were differentially expressed between DLBCLs with high and low p-AKT nuclear expression. We further targeted AKT signaling using a highly selective AKT inhibitor MK-2206 in 26 representative DLBCL cell lines and delineated signaling alterations using a reverse-phase protein array. MK-2206 treatment inhibited lymphoma cell viability, and MK-2206 sensitivity correlated with AKT activation status in DLBCL cells. On MK-2206 treatment, p-AKT levels and downstream targets of AKT signaling were significantly decreased, likely because of the decreased feedback repression; Rictor and phosphatidylinositol 3-kinase expression and other compensatory pathways were also induced. This study demonstrates the clinical and therapeutic implications of AKT hyperactivation in DLBCL and suggests that AKT inhibitors need to be combined with other targeted agents for DLBCL to achieve optimal clinical efficacy. AKT signaling is important for proliferation and survival of tumor cells. The clinical significance of AKT activation in diffuse large B-cell lymphoma (DLBCL) is not well analyzed. Here, we assessed expression of phosphorylated AKT (p-AKT) in 522 DLBCL patients. We found that high levels of p-AKT nuclear expression, observed in 24.3% of the study cohort, were associated with significantly worse progression-free survival and Myc and Bcl-2 overexpression. However, multivariate analysis indicated that AKT hyperactivation was not an independent factor. miRNA profiling analysis demonstrated that 63 miRNAs directly or indirectly related to the phosphatidylinositol 3-kinase/AKT/mechanistic target of rapamycin pathway were differentially expressed between DLBCLs with high and low p-AKT nuclear expression. We further targeted AKT signaling using a highly selective AKT inhibitor MK-2206 in 26 representative DLBCL cell lines and delineated signaling alterations using a reverse-phase protein array. MK-2206 treatment inhibited lymphoma cell viability, and MK-2206 sensitivity correlated with AKT activation status in DLBCL cells. On MK-2206 treatment, p-AKT levels and downstream targets of AKT signaling were significantly decreased, likely because of the decreased feedback repression; Rictor and phosphatidylinositol 3-kinase expression and other compensatory pathways were also induced. This study demonstrates the clinical and therapeutic implications of AKT hyperactivation in DLBCL and suggests that AKT inhibitors need to be combined with other targeted agents for DLBCL to achieve optimal clinical efficacy.AKT signaling is important for proliferation and survival of tumor cells. The clinical significance of AKT activation in diffuse large B-cell lymphoma (DLBCL) is not well analyzed. Here, we assessed expression of phosphorylated AKT (p-AKT) in 522 DLBCL patients. We found that high levels of p-AKT nuclear expression, observed in 24.3% of the study cohort, were associated with significantly worse progression-free survival and Myc and Bcl-2 overexpression. However, multivariate analysis indicated that AKT hyperactivation was not an independent factor. miRNA profiling analysis demonstrated that 63 miRNAs directly or indirectly related to the phosphatidylinositol 3-kinase/AKT/mechanistic target of rapamycin pathway were differentially expressed between DLBCLs with high and low p-AKT nuclear expression. We further targeted AKT signaling using a highly selective AKT inhibitor MK-2206 in 26 representative DLBCL cell lines and delineated signaling alterations using a reverse-phase protein array. MK-2206 treatment inhibited lymphoma cell viability, and MK-2206 sensitivity correlated with AKT activation status in DLBCL cells. On MK-2206 treatment, p-AKT levels and downstream targets of AKT signaling were significantly decreased, likely because of the decreased feedback repression; Rictor and phosphatidylinositol 3-kinase expression and other compensatory pathways were also induced. This study demonstrates the clinical and therapeutic implications of AKT hyperactivation in DLBCL and suggests that AKT inhibitors need to be combined with other targeted agents for DLBCL to achieve optimal clinical efficacy. |
| Author | Jabbar, Kausar J. Manyam, Ganiraju C. Dybkær, Karen Montes-Moreno, Santiago Li, Yong Visco, Carlo Wang, Jinfen Bhagat, Govind Wang, Jing Ponzoni, Maurilio Shen, Qi Medeiros, L. Jeffrey Pham, Lan V. Tzankov, Alexandar Xu-Monette, Zijun Y. Hsi, Eric D. Young, Ken H. Ferreri, Andrés J.M. van Krieken, J. Han Wang, Shi Tam, Wayne Møller, Michael B. Piris, Miguel A. |
| AuthorAffiliation | Department of Cancer Biology, Cleveland Clinic, Lerner Research Institute, Cleveland, Ohio Department of Pathology, Cleveland Clinic, Cleveland, Ohio University of Texas School of Medicine, Graduate School of Biomedical Sciences, Houston, Texas Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas Department of Pathology and Cell Biology, Columbia University Medical Center and New York Presbyterian Hospital, New York, New York Department of Pathology, Shanxi Cancer Hospital, Shanxi, China Department of Pathology, National University Hospital, Singapore Department of Pathology, Weill Medical College of Cornell University, New York, New York Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands San Raffaele H. Scientific Institute, Milan, Italy Department of Pathology, University Hospital, Basel, |
| AuthorAffiliation_xml | – name: Department of Pathology, Hospital Universitario Marques de Valdecilla, Santander, Spain – name: Department of Pathology, Weill Medical College of Cornell University, New York, New York – name: Department of Pathology, Odense University Hospital, Odense, Denmark – name: University of Texas School of Medicine, Graduate School of Biomedical Sciences, Houston, Texas – name: Department of Pathology, National University Hospital, Singapore – name: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas – name: San Raffaele H. Scientific Institute, Milan, Italy – name: Department of Cancer Biology, Cleveland Clinic, Lerner Research Institute, Cleveland, Ohio – name: Department of Pathology and Cell Biology, Columbia University Medical Center and New York Presbyterian Hospital, New York, New York – name: Department of Pathology, Shanxi Cancer Hospital, Shanxi, China – name: Department of Pathology, University Hospital, Basel, Switzerland – name: Department of Pathology, Cleveland Clinic, Cleveland, Ohio – name: Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands – name: Department of Hematology, Aalborg University Hospital, Aalborg, Denmark – name: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas – name: Department of Hematology, San Bortolo Hospital, Vicenza, Italy |
| Author_xml | – sequence: 1 givenname: Jinfen surname: Wang fullname: Wang, Jinfen organization: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 2 givenname: Zijun Y. surname: Xu-Monette fullname: Xu-Monette, Zijun Y. organization: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 3 givenname: Kausar J. surname: Jabbar fullname: Jabbar, Kausar J. organization: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 4 givenname: Qi surname: Shen fullname: Shen, Qi organization: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 5 givenname: Ganiraju C. surname: Manyam fullname: Manyam, Ganiraju C. organization: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 6 givenname: Alexandar surname: Tzankov fullname: Tzankov, Alexandar organization: Department of Pathology, University Hospital, Basel, Switzerland – sequence: 7 givenname: Carlo surname: Visco fullname: Visco, Carlo organization: Department of Hematology, San Bortolo Hospital, Vicenza, Italy – sequence: 8 givenname: Jing surname: Wang fullname: Wang, Jing organization: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 9 givenname: Santiago surname: Montes-Moreno fullname: Montes-Moreno, Santiago organization: Department of Pathology, Hospital Universitario Marques de Valdecilla, Santander, Spain – sequence: 10 givenname: Karen surname: Dybkær fullname: Dybkær, Karen organization: Department of Hematology, Aalborg University Hospital, Aalborg, Denmark – sequence: 11 givenname: Wayne surname: Tam fullname: Tam, Wayne organization: Department of Pathology, Weill Medical College of Cornell University, New York, New York – sequence: 12 givenname: Govind orcidid: 0000-0001-6250-048X surname: Bhagat fullname: Bhagat, Govind organization: Department of Pathology and Cell Biology, Columbia University Medical Center and New York Presbyterian Hospital, New York, New York – sequence: 13 givenname: Eric D. surname: Hsi fullname: Hsi, Eric D. organization: Department of Pathology, Cleveland Clinic, Cleveland, Ohio – sequence: 14 givenname: J. Han surname: van Krieken fullname: van Krieken, J. Han organization: Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands – sequence: 15 givenname: Maurilio surname: Ponzoni fullname: Ponzoni, Maurilio organization: San Raffaele H. Scientific Institute, Milan, Italy – sequence: 16 givenname: Andrés J.M. surname: Ferreri fullname: Ferreri, Andrés J.M. organization: San Raffaele H. Scientific Institute, Milan, Italy – sequence: 17 givenname: Shi surname: Wang fullname: Wang, Shi organization: Department of Pathology, National University Hospital, Singapore – sequence: 18 givenname: Michael B. orcidid: 0000-0003-2041-3630 surname: Møller fullname: Møller, Michael B. organization: Department of Pathology, Odense University Hospital, Odense, Denmark – sequence: 19 givenname: Miguel A. surname: Piris fullname: Piris, Miguel A. organization: Department of Pathology, Hospital Universitario Marques de Valdecilla, Santander, Spain – sequence: 20 givenname: L. Jeffrey orcidid: 0000-0001-6577-8006 surname: Medeiros fullname: Medeiros, L. Jeffrey organization: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 21 givenname: Yong surname: Li fullname: Li, Yong organization: Department of Cancer Biology, Cleveland Clinic, Lerner Research Institute, Cleveland, Ohio – sequence: 22 givenname: Lan V. surname: Pham fullname: Pham, Lan V. organization: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 23 givenname: Ken H. surname: Young fullname: Young, Ken H. email: khyoung@mdanderson.org organization: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/28627414$$D View this record in MEDLINE/PubMed |
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| Copyright | 2017 American Society for Investigative Pathology Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. 2017 American Society for Investigative Pathology |
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| SubjectTerms | Apoptosis Cell Line, Tumor Cell Proliferation - drug effects Disease Progression Disease-Free Survival Female Gene Expression Profiling Gene Expression Regulation, Neoplastic - drug effects Heterocyclic Compounds, 3-Ring - pharmacology Humans Lymphoma, Large B-Cell, Diffuse - drug therapy Lymphoma, Large B-Cell, Diffuse - metabolism Lymphoma, Large B-Cell, Diffuse - mortality Male MicroRNAs - metabolism Middle Aged Phosphorylation - drug effects Prognosis Protein Kinase Inhibitors - pharmacology Proto-Oncogene Proteins c-akt - metabolism Regular Signal Transduction - drug effects Survival Rate |
| Title | AKT Hyperactivation and the Potential of AKT-Targeted Therapy in Diffuse Large B-Cell Lymphoma |
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