McNamara Molly C, Hosios Aaron M, Torrence Margaret E, Zhao Ting, Fraser Cameron, Wilkinson Meghan, Kwiatkowski David J, Henske Elizabeth P, Wu Chin-Lee, Sarosiek Kristopher A, Valvezan Alexander J, Manning Brendan D
Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, 677 Huntington Avenue, Boston, MA, USA.
Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
iScience. 2022 Oct 28;25(11):105458. doi: 10.1016/j.isci.2022.105458. eCollection 2022 Nov 18.
mTORC1 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-X for survival, thereby altering susceptibility to BH3 mimetics that target specific pro-survival BCL-2 proteins. The BCL-2/BCL-X inhibitor 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.
mTORC1在癌症以及由TSC复合物功能丧失性突变引起的遗传性肿瘤综合征结节性硬化症（TSC）中异常激活，TSC复合物是mTORC1的负调节因子。临床批准的mTORC1抑制剂，如雷帕霉素，会产生细胞生长抑制作用，无法消除肿瘤且作用迅速可逆。我们试图确定mTORC1对内在凋亡核心调节因子的影响。在TSC2缺陷的细胞和肿瘤中，我们发现mTORC1抑制剂将细胞生存依赖从MCL-1转变为BCL-2和BCL-X，从而改变了对靶向特定促生存BCL-2蛋白的BH3模拟物的敏感性。BCL-2/BCL-X抑制剂ABT-263与雷帕霉素协同作用，在TSC缺陷细胞和TSC小鼠肿瘤模型中诱导凋亡，从而产生更完全和持久的反应。这些数据揭示了mTORC1下游凋亡机制调节中的治疗脆弱性，这促进了对雷帕霉素的细胞毒性反应。
