文章基本信息

标题：Reciprocal effects of mTOR inhibitors on pro-survival proteins dictate therapeutic responses in tuberous sclerosis complex
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作者：Molly C. McNamara ; Aaron M. Hosios ; Margaret E. Torrence 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2022
卷号：25
期号：11
页码：1-23
DOI：10.1016/j.isci.2022.105458
语种：English
出版社：Elsevier
摘要：SummarymTORC1 is aberrantly activated in cancer and in the genetic tumor syndrome tuberous sclerosis complex (TSC), which is caused by loss-of-function mutations in the TSC complex, a negative regulator of mTORC1. Clinically approved mTORC1 inhibitors, such as rapamycin, elicit a cytostatic effect that fails to eliminate tumors and is rapidly reversible. We sought to determine the effects of mTORC1 on the core regulators of intrinsic apoptosis. In TSC2-deficient cells and tumors, we find that mTORC1 inhibitors shift cellular dependence from MCL-1 to BCL-2 and BCL-XLfor survival, thereby altering susceptibility to BH3 mimetics that target specific pro-survival BCL-2 proteins. The BCL-2/BCL-XLinhibitor ABT-263 synergizes with rapamycin to induce apoptosis in TSC-deficient cells and in a mouse tumor model of TSC, resulting in a more complete and durable response. These data expose a therapeutic vulnerability in regulation of the apoptotic machinery downstream of mTORC1 that promotes a cytotoxic response to rapamycin.Graphical abstractDisplay OmittedHighlights•mTORC1 inhibition alters expression of BCL-2 family proteins in TSC-deficient cells•mTORC1 inhibitors shift cellular dependence from MCL-1 to BCL-2/BCL-XLfor survival•ABT-263 synergizes with mTORC1 inhibitors in TSC-deficient mouse and human cells•ABT-263 improves the anti-tumor durability of rapamycin in a TSC tumor modelBiological sciences; Cancer; Cell biology; Molecular biology