title: Evaluation of the in vivo safety profiles of Rictor inhibition using a zebrafish model.
abstract: The mammalian target of rapamycin (mTOR), which assembles into two distinct multiprotein complexes, called mTORC1 and mTORC2, is known as a central regulator of cellular proliferation and maturation. Rictor is one of the key components of mTORC2 and acts as a scaffolding protein to maintain and stabilize mTORC2. Currently, mTORC2 and/or Rictor are increasingly being recognized as attractive targets for novel modalities of anti-cancer therapy. Unfortunately, the safety profile of Rictor- or mTORC2-targeting strategies has been poorly understood due to the lack of an ideal animal model. In the present study, we used zebrafish as an in vivo model system to evaluate the safety of Rictor inhibition. Our data showed that the Rictor of zebrafish was identified to have high sequence homology with mouse Rictor and human Rictor, which validates the rationale of using zebrafish as a research model. Rictor was dispensable in neonatal hematopoiesis and angiogenesis and was not required for vasculogenesis and other organs. These data are consistent with those of previous observations of using tissue-specific Rictor knockout mice model and have potentially important clinical implications. Our findings highlight a good in vivo safety profile for Rictor- or mTORC2-targeting therapy and point to the feasibility and advantages of using the zebrafish model to evaluate the safety of the therapeutic target.
authors.forename: Yang
authors.initials: Y
authors.lastname: Cao
authors.forename: Lijun
authors.initials: L
authors.lastname: Jiang
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Zhou
authors.forename: Na
authors.initials: N
authors.lastname: Wang
authors.forename: Peilin
authors.initials: P
authors.lastname: Zhang
authors.forename: Yuting
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P.R. China. jfzhou@tjh.tjmu.edu.cn.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D005240:Feasibility Studies; D055785:Gene Knockdown Techniques; D006410:Hematopoiesis / Q000502:physiology; D006801:Humans; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D023421:Models, Animal; D046912:Multiprotein Complexes / Q000235:genetics*; D018919:Neovascularization, Physiologic / Q000502:physiology; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D017422:Sequence Analysis, DNA; D013045:Species Specificity; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D046912:Multiprotein Complexes; C492571:RICTOR protein, human; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D029961:Zebrafish Proteins; C525637:rictor protein, mouse; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases