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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.

Author information

1
Università della Svizzera Italiana (USI), Institute of Oncology Research (IOR), Bellinzona, Switzerland.
2
Dalle Molle Institute for Artificial Intelligence (IDSIA), Manno, Switzerland.
3
Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
4
PIQUR Therapeutics AG, Basel, Switzerland.
5
Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland.
6
IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
7
Department of Biomedicine, University of Basel, Basel, Switzerland.
8
Department of Oncology, University Hospital Basel, Basel, Switzerland.
9
Cytogenetics Laboratory, Ente Ospedaliero Cantonale, Bellinzona, Switzerland.
10
Clinical and Experimental Onco-Hematology Unit, IRCCS-Centro di Riferimento Oncologico, Aviano, Italy.
11
Università della Svizzera Italiana (USI), Institute of Oncology Research (IOR), Bellinzona, Switzerland. frbertoni@mac.com.
#
Contributed equally

Abstract

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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