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Clin Cancer Res. 2018 Jan 1;24(1):120-129. doi: 10.1158/1078-0432.CCR-17-1041. Epub 2017 Oct 24.

PQR309 Is a Novel Dual PI3K/mTOR Inhibitor with Preclinical Antitumor Activity in Lymphomas as a Single Agent and in Combination Therapy.

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Università della Svizzera Italiana (USI), Institute of Oncology Research (IOR), Bellinzona, Switzerland.
Dalle Molle Institute for Artificial Intelligence (IDSIA), Manno, Switzerland.
Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
PIQUR Therapeutics AG, Basel, Switzerland.
Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland.
IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Department of Biomedicine, University of Basel, Basel, Switzerland.
Department of Oncology, University Hospital Basel, Basel, Switzerland.
Cytogenetics Laboratory, Ente Ospedaliero Cantonale, Bellinzona, Switzerland.
Clinical and Experimental Onco-Hematology Unit, IRCCS-Centro di Riferimento Oncologico, Aviano, Italy.
Università della Svizzera Italiana (USI), Institute of Oncology Research (IOR), Bellinzona, Switzerland.
Contributed equally


Purpose: Activation of the PI3K/mTOR signaling pathway is recurrent in different lymphoma types, and pharmacologic inhibition of the PI3K/mTOR pathway has shown activity in lymphoma patients. Here, we extensively characterized the in vitro and in vivo activity and the mechanism of action of PQR309 (bimiralisib), a novel oral selective dual PI3K/mTOR inhibitor under clinical evaluation, in preclinical lymphoma models.Experimental Design: This study included preclinical in vitro activity screening on a large panel of cell lines, both as single agent and in combination, validation experiments on in vivo models and primary cells, proteomics and gene-expression profiling, and comparison with other signaling inhibitors.Results: PQR309 had in vitro antilymphoma activity as single agent and in combination with venetoclax, panobinostat, ibrutinib, lenalidomide, ARV-825, marizomib, and rituximab. Sensitivity to PQR309 was associated with specific baseline gene-expression features, such as high expression of transcripts coding for the BCR pathway. Combining proteomics and RNA profiling, we identified the different contribution of PQR309-induced protein phosphorylation and gene expression changes to the drug mechanism of action. Gene-expression signatures induced by PQR309 and by other signaling inhibitors largely overlapped. PQR309 showed activity in cells with primary or secondary resistance to idelalisib.Conclusions: On the basis of these results, PQR309 appeared as a novel and promising compound that is worth developing in the lymphoma setting. Clin Cancer Res; 24(1); 120-9. ©2017 AACR.

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