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Functional genomics identifies new synergistic therapies for retinoblastoma.

Authors
  • Aubry, Arthur1, 2
  • Pearson, Joel D1, 2, 3
  • Huang, Katherine1
  • Livne-Bar, Izhar3, 4
  • Ahmad, Mohammad1
  • Jagadeesan, Madhavan5, 6
  • Khetan, Vikas7
  • Ketela, Troy8
  • Brown, Kevin R8
  • Yu, Tao1
  • Lu, Suying1
  • Wrana, Jeffrey L1, 9
  • Moffat, Jason8, 9
  • Bremner, Rod10, 11, 12
  • 1 Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health, Toronto, ON, Canada. , (Canada)
  • 2 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. , (Canada)
  • 3 Department of Ophthalmology and Vision Science, University of Toronto, Toronto, ON, Canada. , (Canada)
  • 4 Krembil Research Institute, University Health Network, Toronto, ON, Canada. , (Canada)
  • 5 Vision Research Foundation, Sankara Nethralaya, Chennai, India. , (India)
  • 6 Dualhelix Genetic Diagnostics, Chennai, India. , (India)
  • 7 Department of Vitroretina and Ocular Oncology, Sankara Nethralaya, Chennai, India. , (India)
  • 8 Donnelly Centre, University of Toronto, Toronto, ON, Canada. , (Canada)
  • 9 Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. , (Canada)
  • 10 Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health, Toronto, ON, Canada. [email protected] , (Canada)
  • 11 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. [email protected] , (Canada)
  • 12 Department of Ophthalmology and Vision Science, University of Toronto, Toronto, ON, Canada. [email protected] , (Canada)
Type
Published Article
Journal
Oncogene
Publisher
Nature Publishing Group UK
Publication Date
Jun 22, 2020
Identifiers
DOI: 10.1038/s41388-020-1372-7
PMID: 32572160
Source
Medline
Language
English
License
Unknown

Abstract

Local intravitreal or intra-arterial chemotherapy has improved therapeutic success for the pediatric cancer retinoblastoma (RB), but toxicity remains a major caveat. RB initiates primarily with RB1 loss or, rarely, MYCN amplification, but the critical downstream networks are incompletely understood. We set out to uncover perturbed molecular hubs, identify synergistic drug combinations to target these vulnerabilities, and expose and overcome drug resistance. We applied dynamic transcriptomic analysis to identify network hubs perturbed in RB versus normal fetal retina, and performed in vivo RNAi screens in RB1null and RB1wt;MYCNamp orthotopic xenografts to pinpoint essential hubs. We employed in vitro and in vivo studies to validate hits, define mechanism, develop new therapeutic modalities, and understand drug resistance. We identified BRCA1 and RAD51 as essential for RB cell survival. Their oncogenic activity was independent of BRCA1 functions in centrosome, heterochromatin, or ROS regulation, and instead linked to DNA repair. RAD51 depletion or inhibition with the small molecule inhibitor, B02, killed RB cells in a Chk1/Chk2/p53-dependent manner. B02 further synergized with clinically relevant topotecan (TPT) to engage this pathway, activating p53-BAX mediated killing of RB but not human retinal progenitor cells. Paradoxically, a B02/TPT-resistant tumor exhibited more DNA damage than sensitive RB cells. Resistance reflected dominance of the p53-p21 axis, which mediated cell cycle arrest instead of death. Deleting p21 or applying the BCL2/BCL2L1 inhibitor Navitoclax re-engaged the p53-BAX axis, and synergized with B02, TPT or both to override resistance. These data expose new synergistic therapies to trigger p53-induced killing in diverse RB subtypes.

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