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Blockade of Oncogenic NOTCH1 with the SERCA Inhibitor CAD204520 in T Cell Acute Lymphoblastic Leukemia

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  • Matteo Marchesini, University of Parma
  • ,
  • Andrea Gherli, University of Parma
  • ,
  • Anna Montanaro, University of Parma
  • ,
  • Laura Patrizi, University of Perugia
  • ,
  • Claudia Sorrentino, University of Parma
  • ,
  • Luca Pagliaro, University of Parma
  • ,
  • Chiara Rompietti, University of Perugia
  • ,
  • Samuel Kitara, Harvard Medical School
  • ,
  • Sabine Heit, University of Oxford
  • ,
  • Claus E. Olesen
  • Jesper V. Møller
  • Monia Savi, University of Parma
  • ,
  • Leonardo Bocchi, University of Parma
  • ,
  • Rocchina Vilella, University of Parma
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  • Federica Rizzi, University of Parma, INBB – Biostructures and Biosystems National Institute
  • ,
  • Marilena Baglione, University of Parma
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  • Giorgia Rastelli, University of Parma
  • ,
  • Caterina Loiacono, University of Parma
  • ,
  • Roberta La Starza, University of Perugia
  • ,
  • Cristina Mecucci, University of Perugia
  • ,
  • Kimberly Stegmaier, Broad Institute, Harvard Medical School
  • ,
  • Franco Aversa, University of Parma
  • ,
  • Donatella Stilli, University of Parma
  • ,
  • Anne Marie Lund Winther, Cado Biotechnology IvS
  • ,
  • Paolo Sportoletti, University of Perugia
  • ,
  • Maike Bublitz, University of Oxford
  • ,
  • William Dalby-Brown, Cado Biotechnology IvS
  • ,
  • Giovanni Roti, University of Parma

The identification of SERCA (sarco/endoplasmic reticulum calcium ATPase) as a target for modulating gain-of-function NOTCH1 mutations in Notch-dependent cancers has spurred the development of this compound class for cancer therapeutics. Despite the innate toxicity challenge associated with SERCA inhibition, we identified CAD204520, a small molecule with better drug-like properties and reduced off-target Ca2+ toxicity compared with the SERCA inhibitor thapsigargin. In this work, we describe the properties and complex structure of CAD204520 and show that CAD204520 preferentially targets mutated over wild-type NOTCH1 proteins in T cell acute lymphoblastic leukemia (T-ALL) and mantle cell lymphoma (MCL). Uniquely among SERCA inhibitors, CAD204520 suppresses NOTCH1-mutated leukemic cells in a T-ALL xenografted model without causing cardiac toxicity. This study supports the development of SERCA inhibitors for Notch-dependent cancers and extends their application to cases with isolated mutations in the PEST degradation domain of NOTCH1, such as MCL or chronic lymphocytic leukemia (CLL). Clinical translation of SERCA inhibitors has been hampered by the risk of adverse cardiac events. In this work, Marchesini and Gherli et al. identified a tolerable oral available SERCA inhibitor, CAD204520, and showed that modulation of clinically relevant NOTCH1 mutations in T cell acute lymphoblastic leukemia and mantle cell lymphoma.

OriginalsprogEngelsk
TidsskriftCell Chemical Biology
Vol/bind27
Nummer6
Sider (fra-til)678-697.e13
ISSN2451-9456
DOI
StatusUdgivet - jun. 2020

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