PMID- 35525984 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220716 IS - 2045-3701 (Print) IS - 2045-3701 (Electronic) IS - 2045-3701 (Linking) VI - 12 IP - 1 DP - 2022 May 7 TI - AKT inhibition in the central nervous system induces signaling defects resulting in psychiatric symptomatology. PG - 56 LID - 10.1186/s13578-022-00793-8 [doi] LID - 56 AB - 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 x 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. CI - (c) 2022. The Author(s). FAU - Tsimberidou, Apostolia-Maria AU - Tsimberidou AM AUID- ORCID: 0000-0003-2713-233X AD - Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Boulevard, Houston, TX, 77030, USA. atsimber@mdanderson.org. FAU - Skliris, Antonis AU - Skliris A AD - Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA, 02111, USA. FAU - Valentine, Alan AU - Valentine A AD - Department of Psychiatry, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. FAU - Shaw, Jamie AU - Shaw J AD - EMD Serono Billerica (a Business of Merck KGaA), 01821, Darmstadt, MA, Germany. FAU - Hering, Ursula AU - Hering U AD - Merck KGaA, 64293, Darmstadt, Germany. FAU - Vo, Henry Hiep AU - Vo HH AD - Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Unit 455, 1515 Holcombe Boulevard, Houston, TX, 77030, USA. FAU - Chan, Tung On AU - Chan TO AD - Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USA. FAU - Armen, Roger S AU - Armen RS AD - Department of Pharmaceutical Sciences, College of Pharmacy, Thomas Jefferson University, Philadelphia, PA, 19107, USA. FAU - Cottrell, Jeffrey R AU - Cottrell JR AD - Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. FAU - Pan, Jen Q AU - Pan JQ AD - Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. FAU - Tsichlis, Philip N AU - Tsichlis PN AD - Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA, 02111, USA. Philip.Tsichlis@osumc.edu. AD - Department of Cancer Biology and Genetics, College of Medicine, and the Ohio State University Comprehensive Cancer Center, The Ohio State University, 460 W 12th Ave, Columbus, OH, 43210, USA. Philip.Tsichlis@osumc.edu. LA - eng GR - R01CAN186729 to Philip N. Tsichlis (Ohio State University)/National Institutes of Health/National Cancer Institute/ GR - P30 CA016672 (The University of Texas MD Anderson Cancer Center)/National Institutes of Health/National Cancer Institute/ GR - P30 CA016058 (Ohio State University)/National Institutes of Health/National Cancer Institute/ PT - Journal Article DEP - 20220507 PL - England TA - Cell Biosci JT - Cell & bioscience JID - 101561195 PMC - PMC9080159 OTO - NOTNLM OT - AKT OT - Advanced cancer OT - Central nervous system OT - Clinical trial OT - Mental illness OT - PI3K COIS- The authors have the following financial relationships to disclose: Apostolia M. Tsimberidou: Clinical Trial Research Funding (received through the institution): OBI Pharma, IMMATICS, Parker Institute for Cancer Immunotherapy, Agenus, Tempus, Tvardi, Boston Biomedical, Karus Therapeutics; Consulting or Advisory Role: Vincerx, Diaccurate. Alan Valentine: Common stock in Merck and Co. Jamie Shaw is an employee of EMD Serono. Inc. (a business of Merck KGaA, Darmstadt, Germany). Ursula Hering is an employee of Merck KGaA, Darmstadt, Germany. Drs. Skliris, Vo, Chan, Armen, Cottrell, and Pen declare no relevant conflict of interests. EDAT- 2022/05/08 06:00 MHDA- 2022/05/08 06:01 PMCR- 2022/05/07 CRDT- 2022/05/07 23:37 PHST- 2022/01/11 00:00 [received] PHST- 2022/04/18 00:00 [accepted] PHST- 2022/05/07 23:37 [entrez] PHST- 2022/05/08 06:00 [pubmed] PHST- 2022/05/08 06:01 [medline] PHST- 2022/05/07 00:00 [pmc-release] AID - 10.1186/s13578-022-00793-8 [pii] AID - 793 [pii] AID - 10.1186/s13578-022-00793-8 [doi] PST - epublish SO - Cell Biosci. 2022 May 7;12(1):56. doi: 10.1186/s13578-022-00793-8.