Reciprocal effects of mTOR inhibitors on pro-survival proteins dictate therapeutic responses in tuberous sclerosis complex
Molly C. McNamara,
Aaron M. Hosios,
Margaret E. Torrence,
Ting Zhao,
Cameron Fraser,
Meghan Wilkinson,
David J. Kwiatkowski,
Elizabeth P. Henske,
Chin-Lee Wu,
Kristopher A. Sarosiek,
Alexander J. Valvezan,
Brendan D. Manning
Affiliations
Molly C. McNamara
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
Aaron M. Hosios
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
Margaret E. Torrence
Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, 677 Huntington Avenue, Boston, MA, USA
Ting Zhao
Department of Urology, Massachusetts General Hospital, Boston, MA, USA; Department of Pathology, Harvard Medical School, Boston, MA, USA
Cameron Fraser
Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA 02215, USA
Meghan Wilkinson
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
David J. Kwiatkowski
Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
Elizabeth P. Henske
Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
Chin-Lee Wu
Department of Urology, Massachusetts General Hospital, Boston, MA, USA; Department of Pathology, Harvard Medical School, Boston, MA, USA
Kristopher A. Sarosiek
Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA 02215, USA
Alexander J. Valvezan
Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, 677 Huntington Avenue, Boston, MA, USA
Brendan D. Manning
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; Corresponding author
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.
