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Journal article

The novel TORC1/2 kinase inhibitor PQR620 has anti-tumor activity in lymphomas as a single agent and in combination with venetoclax

  • Tarantelli, Chiara Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
  • Gaudio, Eugenio Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
  • Hillmann, Petra PIQUR Therapeutics AG, 4057 Basel, Switzerland
  • Spriano, Filippo Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
  • Sartori, Giulio Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
  • Aresu, Luca Dipartimento di Scienze Veterinarie, Università degli Studi di Torino, 10095 Grugliasco (TO), Italy
  • Cascione, Luciano Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Swiss Institute of Bioinformatics (SIB), 1015 Lausanne, Switzerland
  • Rageot, Denise Department of Biomedicine, University of Basel, 4056 Basel, Switzerland
  • Kwee, Ivo Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Swiss Institute of Bioinformatics (SIB), 1015 Lausanne, Switzerland
  • Beaufils, Florent PIQUR Therapeutics AG, 4057 Basel, Switzerland
  • Zucca, Emanuele Oncology Institute of Southern Switzerland, 6500 Bellinzona, Switzerland
  • Stathis, Anastasios Oncology Institute of Southern Switzerland, 6500 Bellinzona, Switzerland
  • Wymann, Matthias P. Department of Biomedicine, University of Basel, 4056 Basel, Switzerland
  • Cmiljanovic, Vladimir PIQUR Therapeutics AG, 4057 Basel, Switzerland
  • Fabbro, Doriano PIQUR Therapeutics AG, 4057 Basel, Switzerland
  • Bertoni, Francesco Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
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    04.06.2019
Published in:
  • Cancers. - 2019, vol. 11, no. 6, p. 775
Lymphoma
mTORC1
mTORC2
Venetoclax
Mantle cell lymphoma
Diffuse large B cell lymphoma
English The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling cascade is an important therapeutic target for lymphomas. Rapamycin-derivates as allosteric mTOR complex 1 (TORC1) inhibitors have shown moderate preclinical and clinical anti-lymphoma activity. Here, we assessed the anti-tumor activity of PQR620, a novel brain penetrant dual TORC1/2 inhibitor, in 56 lymphoma cell lines. We observed anti-tumor activity across 56 lymphoma models with a median IC50 value of 250 nM after 72 h of exposure. PQR620 was largely cytostatic, but the combination with the BCL2 inhibitor venetoclax led to cytotoxicity. Both the single agent and the combination data were validated in xenograft models. The data support further evaluation of PQR620 as a single agent or in combination with venetoclax.
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  • English
Classification
Medicine
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https://n2t.net/ark:/12658/srd1319122
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