2. Academic Validation
  3. Reciprocal effects of mTOR inhibitors on pro-survival proteins dictate therapeutic responses in tuberous sclerosis complex

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

  • iScience. 2022 Oct 28;25(11):105458. doi: 10.1016/j.isci.2022.105458.
Molly C McNamara 1 2,  Aaron M Hosios 1 2,  Margaret E Torrence 1,  Ting Zhao 3 4,  Cameron Fraser 5,  Meghan Wilkinson 1 2,  David J Kwiatkowski 6,  Elizabeth P Henske 6,  Chin-Lee Wu 3 4,  Kristopher A Sarosiek 5,  Alexander J Valvezan 1,  Brendan D Manning 1 2
Affiliations

Affiliations

  • 1 Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, 677 Huntington Avenue, Boston, MA, USA.
  • 2 Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
  • 3 Department of Urology, Massachusetts General Hospital, Boston, MA, USA.
  • 4 Department of Pathology, Harvard Medical School, Boston, MA, USA.
  • 5 Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA 02215, USA.
  • 6 Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
PMID: 36388985 DOI: 10.1016/j.isci.2022.105458
Abstract

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.

Keywords

Biological sciences; Cancer; Cell biology; Molecular biology.

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