AKT inhibition in the central nervous system induces signaling defects resulting in psychiatric symptomatology
Abstract Background Changes in the expression and activity of the AKT oncogene play an important role in psychiatric disease. We present translational data assessing the role of AKT in psychiatric symptoms. Methods (1) We assessed the protein activity of an AKT3 mutant harboring a PH domain mutation...
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| Format: | Article |
| Language: | English |
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BMC
2022-05-01
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| Series: | Cell & Bioscience |
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| Online Access: | https://doi.org/10.1186/s13578-022-00793-8 |
| _version_ | 1829114879996329984 |
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| author | Apostolia-Maria Tsimberidou Antonis Skliris Alan Valentine Jamie Shaw Ursula Hering Henry Hiep Vo Tung On Chan Roger S. Armen Jeffrey R. Cottrell Jen Q. Pan Philip N. Tsichlis |
| author_facet | Apostolia-Maria Tsimberidou Antonis Skliris Alan Valentine Jamie Shaw Ursula Hering Henry Hiep Vo Tung On Chan Roger S. Armen Jeffrey R. Cottrell Jen Q. Pan Philip N. Tsichlis |
| author_sort | Apostolia-Maria Tsimberidou |
| collection | DOAJ |
| description | Abstract Background Changes in the expression and activity of the AKT oncogene play an important role in psychiatric disease. We present translational data assessing the role of AKT in psychiatric symptoms. Methods (1) We assessed the protein activity of an AKT3 mutant harboring a PH domain mutation (Q60H) detected in a patient with schizophrenia, the corresponding AKT1 mutant (Q61H), and wild-type AKT1 and AKT3 transduced in AKT-null mouse fibroblasts and modeled the Q61H mutation onto the crystal structure of the Akt1 PH domain. (2) We analyzed the results of earlier genome-wide association studies to determine the distribution of schizophrenia-associated single-nucleotide polymorphisms (SNPs) in the AKT3 gene. (3) We analyzed the psychiatric adverse events (AEs) of patients treated with M2698 (p70S6K/AKT1/AKT3 inhibitor) and with other PI3K/AKT/mTOR pathway inhibitors. Results (1) Proteins encoded by AKT3 (AKT3Q60H) and AKT1 (AKT1Q61H) mutants had lower kinase activity than those encoded by wild-type AKT3 and AKT1, respectively. Molecular modeling of the AKT1-Q61H mutant suggested conformational changes that may reduce the binding of D3-phosphorylated phosphoinositides to the PH domain. (2) We identified multiple SNPs in the AKT3 gene that were strongly associated with schizophrenia (p < 0.5 × 10–8). (3) Psychiatric AEs, mostly insomnia, anxiety, and depression, were noted in 29% of patients treated with M2698. In randomized studies, their incidence was higher in PI3K/AKT/mTOR inhibitor arms compared with placebo arms. All psychiatric AEs were reversible. Conclusions Our data elucidate the incidence and mechanisms of psychiatric AEs in patients treated with PI3K/AKT/mTOR inhibitors and emphasize the need for careful monitoring. |
| first_indexed | 2024-12-12T16:02:29Z |
| format | Article |
| id | doaj.art-db571bc65b8444c39720d8f1d6ebe5cd |
| institution | Directory Open Access Journal |
| issn | 2045-3701 |
| language | English |
| last_indexed | 2024-12-12T16:02:29Z |
| publishDate | 2022-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell & Bioscience |
| spelling | doaj.art-db571bc65b8444c39720d8f1d6ebe5cd2022-12-22T00:19:23ZengBMCCell & Bioscience2045-37012022-05-0112111310.1186/s13578-022-00793-8AKT inhibition in the central nervous system induces signaling defects resulting in psychiatric symptomatologyApostolia-Maria Tsimberidou0Antonis Skliris1Alan Valentine2Jamie Shaw3Ursula Hering4Henry Hiep Vo5Tung On Chan6Roger S. Armen7Jeffrey R. Cottrell8Jen Q. Pan9Philip N. Tsichlis10Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer CenterMolecular Oncology Research Institute, Tufts Medical CenterDepartment of Psychiatry, The University of Texas MD Anderson Cancer CenterEMD Serono Billerica (a Business of Merck KGaA)Merck KGaADepartment of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer CenterCenter for Translational Medicine, Thomas Jefferson UniversityDepartment of Pharmaceutical Sciences, College of Pharmacy, Thomas Jefferson UniversityStanley Center for Psychiatric Research, Broad Institute of MIT and HarvardStanley Center for Psychiatric Research, Broad Institute of MIT and HarvardMolecular Oncology Research Institute, Tufts Medical CenterAbstract Background Changes in the expression and activity of the AKT oncogene play an important role in psychiatric disease. We present translational data assessing the role of AKT in psychiatric symptoms. Methods (1) We assessed the protein activity of an AKT3 mutant harboring a PH domain mutation (Q60H) detected in a patient with schizophrenia, the corresponding AKT1 mutant (Q61H), and wild-type AKT1 and AKT3 transduced in AKT-null mouse fibroblasts and modeled the Q61H mutation onto the crystal structure of the Akt1 PH domain. (2) We analyzed the results of earlier genome-wide association studies to determine the distribution of schizophrenia-associated single-nucleotide polymorphisms (SNPs) in the AKT3 gene. (3) We analyzed the psychiatric adverse events (AEs) of patients treated with M2698 (p70S6K/AKT1/AKT3 inhibitor) and with other PI3K/AKT/mTOR pathway inhibitors. Results (1) Proteins encoded by AKT3 (AKT3Q60H) and AKT1 (AKT1Q61H) mutants had lower kinase activity than those encoded by wild-type AKT3 and AKT1, respectively. Molecular modeling of the AKT1-Q61H mutant suggested conformational changes that may reduce the binding of D3-phosphorylated phosphoinositides to the PH domain. (2) We identified multiple SNPs in the AKT3 gene that were strongly associated with schizophrenia (p < 0.5 × 10–8). (3) Psychiatric AEs, mostly insomnia, anxiety, and depression, were noted in 29% of patients treated with M2698. In randomized studies, their incidence was higher in PI3K/AKT/mTOR inhibitor arms compared with placebo arms. All psychiatric AEs were reversible. Conclusions Our data elucidate the incidence and mechanisms of psychiatric AEs in patients treated with PI3K/AKT/mTOR inhibitors and emphasize the need for careful monitoring.https://doi.org/10.1186/s13578-022-00793-8AKTPI3KAdvanced cancerClinical trialCentral nervous systemMental illness |
| spellingShingle | Apostolia-Maria Tsimberidou Antonis Skliris Alan Valentine Jamie Shaw Ursula Hering Henry Hiep Vo Tung On Chan Roger S. Armen Jeffrey R. Cottrell Jen Q. Pan Philip N. Tsichlis AKT inhibition in the central nervous system induces signaling defects resulting in psychiatric symptomatology Cell & Bioscience AKT PI3K Advanced cancer Clinical trial Central nervous system Mental illness |
| title | AKT inhibition in the central nervous system induces signaling defects resulting in psychiatric symptomatology |
| title_full | AKT inhibition in the central nervous system induces signaling defects resulting in psychiatric symptomatology |
| title_fullStr | AKT inhibition in the central nervous system induces signaling defects resulting in psychiatric symptomatology |
| title_full_unstemmed | AKT inhibition in the central nervous system induces signaling defects resulting in psychiatric symptomatology |
| title_short | AKT inhibition in the central nervous system induces signaling defects resulting in psychiatric symptomatology |
| title_sort | akt inhibition in the central nervous system induces signaling defects resulting in psychiatric symptomatology |
| topic | AKT PI3K Advanced cancer Clinical trial Central nervous system Mental illness |
| url | https://doi.org/10.1186/s13578-022-00793-8 |
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