| First Author | Fan C | Year | 2023 |
| Journal | Leukemia | Volume | 37 |
| Issue | 10 | Pages | 2073-2081 |
| PubMed ID | 37532788 | Mgi Jnum | J:341188 |
| Mgi Id | MGI:7531955 | Doi | 10.1038/s41375-023-01987-w |
| Citation | Fan C, et al. (2023) Kinase-independent role of mTOR and on-/off-target effects of an mTOR kinase inhibitor. Leukemia 37(10):2073-2081 |
| abstractText | mTOR, as a serine/threonine kinase, is a widely pursued anticancer target. Multiple clinical trials of mTOR kinase inhibitors are ongoing, but their specificity and safety features remain lacking. Here, we have employed an inducible kinase-inactive D2338A mTOR knock-in mouse model (mTOR(-/KI)) together with a mTOR conditional knockout model (mTOR(-/-)) to assess the kinase-dependent/-independent function of mTOR in hematopoiesis and the on-/off-target effects of mTOR kinase inhibitor AZD2014. Despite exhibiting many similar phenotypes to mTOR(-/-) mice in hematopoiesis, the mTOR(-/KI) mice survived longer and showed differences in hematopoietic progenitor cells compared to mTOR(-/-) mice, suggesting a kinase-independent function of mTOR in hematopoiesis. Gene expression signatures in hematopoietic stem cells (HSCs) further revealed both kinase-dependent and independent effects of mTOR. AZD2014, a lead mTOR kinase inhibitor, appeared to work mostly on-target in suppressing mTOR kinase activity, mimicking that of mTOR(-/KI) HSCs in transcriptome analysis, but it also induced a small set of off-target responses in mTOR(-/KI) HSCs. In murine and human myeloid leukemia, besides kinase-inhibitory on-target effects, AZD2014 displayed similar off-target and growth-inhibitory cytostatic effects. These studies provide new insights into kinase-dependent/-independent effects of mTOR in hematopoiesis and present a genetic means for precisely assessing the specificity of mTOR kinase inhibitors. |
