Reciprocal effects of mTOR inhibitors on pro-survival proteins dictate therapeutic responses in tuberous sclerosis complex

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 fai...

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Bibliographic Details
Published iniScience Vol. 25; no. 11; p. 105458
Main Authors 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.
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 18.11.2022
Elsevier
Subjects
Biological sciences
Cancer
Cell biology
Molecular biology
Cell biology
Biological sciences
Molecular biology
Cancer
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Summary: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-XL for survival, thereby altering susceptibility to BH3 mimetics that target specific pro-survival BCL-2 proteins. The BCL-2/BCL-XL 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. [Display omitted] •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-XL for 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 model Biological sciences; Cancer; Cell biology; Molecular biology
Bibliography:Present address: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
Present address: Center for Advanced Biotechnology and Medicine, Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, USA
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ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2022.105458