2. Academic Validation
  3. Dual mTORC1/2 inhibition compromises cell defenses against exogenous stress potentiating Obatoclax-induced cytotoxicity in atypical teratoid/rhabdoid tumors

Dual mTORC1/2 inhibition compromises cell defenses against exogenous stress potentiating Obatoclax-induced cytotoxicity in atypical teratoid/rhabdoid tumors

  • Cell Death Dis. 2022 Apr 28;13(4):410. doi: 10.1038/s41419-022-04868-9.
Ashlyn Parkhurst  # 1 2,  Sabrina Z Wang  # 1 2,  Tyler R Findlay 1 2,  Kristen J Malebranche 3,  Arman Odabas 4,  Jesse Alt 5 6,  Micah J Maxwell 1 2,  Harpreet Kaur 1 2,  Cody J Peer 4,  William D Figg 4,  Katherine E Warren 7 8,  Barbara S Slusher 5 6,  Charles G Eberhart 9,  Eric H Raabe 1 2,  Jeffrey A Rubens 10 11
Affiliations

Affiliations

  • 1 Division of Pediatric Oncology, Johns Hopkins University, School of Medicine, 1800 Orleans St, Baltimore, MD, 21287, USA.
  • 2 Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, School of Medicine, 1800 Orleans St, Baltimore, MD, 21287, USA.
  • 3 Division of Cell Biology, Johns Hopkins University, School of Medicine, 1800 Orleans St, Baltimore, MD, 21287, USA.
  • 4 Clinical Pharmacology Program, National Cancer Institute at the National Institutes of Health, 37 Convent Dr, Bethesda, MD, 20892, USA.
  • 5 Johns Hopkins Drug Discovery, Johns Hopkins University, School of Medicine, 1800 Orleans St, Baltimore, MD, 21287, USA.
  • 6 Department of Neurology, Johns Hopkins University, School of Medicine, 1800 Orleans St, Baltimore, MD, 21287, USA.
  • 7 Pediatric Oncology Branch, National Cancer Institute at the National Institutes of Health, 37 Convent Dr, Bethesda, MD, 20892, USA.
  • 8 Dana Farber Cancer Institute (KEW), 450 Brookline Ave, Boston, MA, 02215, USA.
  • 9 Division of Neuropathology, Johns Hopkins University, School of Medicine, 1800 Orleans St, Baltimore, MD, 21287, USA.
  • 10 Division of Pediatric Oncology, Johns Hopkins University, School of Medicine, 1800 Orleans St, Baltimore, MD, 21287, USA. Jrubens6@jhmi.edu.
  • 11 Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, School of Medicine, 1800 Orleans St, Baltimore, MD, 21287, USA. Jrubens6@jhmi.edu.
  • # Contributed equally.
PMID: 35484114 DOI: 10.1038/s41419-022-04868-9
Abstract

Atypical teratoid/rhabdoid tumors (AT/RT) are the most common malignant brain tumors of infancy and have a dismal 4-year event-free survival (EFS) of 37%. We have previously shown that mTOR activation contributes to AT/RT's aggressive growth and poor survival. Targeting the mTOR pathway with the dual mTORC1/2 inhibitor TAK-228 slows tumor growth and extends survival in mice bearing orthotopic xenografts. However, responses are primarily cytostatic with limited durability. The aim of this study is to understand the impact of mTOR inhibitors on AT/RT signaling pathways and design a rational combination therapy to drive a more durable response to this promising therapy. We performed RNASeq, gene expression studies, and protein analyses to identify pathways disrupted by TAK-228. We find that TAK-228 decreases the expression of the transcription factor NRF2 and compromises AT/RT cellular defenses against oxidative stress and Apoptosis. The BH3 mimetic, Obatoclax, is a potent inducer of oxidative stress and Apoptosis in AT/RT. These complementary mechanisms of action drive extensive synergies between TAK-228 and Obatoclax slowing AT/RT cell growth and inducing Apoptosis and cell death. Combination therapy activates the integrative stress response as determined by increased expression of phosphorylated EIF2α, ATF4, and CHOP, and disrupts the protective NOXA.Mcl-1.Bim axis, forcing stressed cells to undergo Apoptosis. Combination therapy is well tolerated in mice bearing orthotopic xenografts of AT/RT, slows tumor growth, and extends median overall survival. This novel combination therapy could be added to standard upfront therapies or used as a salvage therapy for relapsed disease to improve outcomes in AT/RT.

Figures
Products