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

Tarantelli, Chiara; Gaudio, Eugenio; Hillmann, Petra; Spriano, Filippo; Sartori, Giulio; Aresu, Luca; Cascione, Luciano; Rageot, Denise; Kwee, Ivo; Beaufils, Florent; Zucca, Emanuele; Stathis, Anastasios; Wymann, Matthias P.; Cmiljanovic, Vladimir; Fabbro, Doriano; Bertoni, Francesco

doi:10.3390/cancers11060775

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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

04.06.2019

Published in:

Cancers. - 2019, vol. 11, no. 6, p. 775

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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