Evaluation of the in vivo safety profiles of Rictor inhibition using a zebrafish model

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.