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

  • Tarantelli C Università della Svizzera Italiana (USI), Institute of Oncology Research (IOR), Bellinzona, Switzerland.
  • Gaudio E Università della Svizzera Italiana (USI), Institute of Oncology Research (IOR), Bellinzona, Switzerland.
  • Arribas AJ Università della Svizzera Italiana (USI), Institute of Oncology Research (IOR), Bellinzona, Switzerland.
  • Kwee I Università della Svizzera Italiana (USI), Institute of Oncology Research (IOR), Bellinzona, Switzerland.
  • Hillmann P PIQUR Therapeutics AG, Basel, Switzerland.
  • Rinaldi A Università della Svizzera Italiana (USI), Institute of Oncology Research (IOR), Bellinzona, Switzerland.
  • Cascione L Università della Svizzera Italiana (USI), Institute of Oncology Research (IOR), Bellinzona, Switzerland.
  • Spriano F Università della Svizzera Italiana (USI), Institute of Oncology Research (IOR), Bellinzona, Switzerland.
  • Bernasconi E Università della Svizzera Italiana (USI), Institute of Oncology Research (IOR), Bellinzona, Switzerland.
  • Guidetti F Università della Svizzera Italiana (USI), Institute of Oncology Research (IOR), Bellinzona, Switzerland.
  • Carrassa L IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
  • Pittau RB Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland.
  • Beaufils F PIQUR Therapeutics AG, Basel, Switzerland.
  • Ritschard R Department of Oncology, University Hospital Basel, Basel, Switzerland.
  • Rageot D PIQUR Therapeutics AG, Basel, Switzerland.
  • Sele A Department of Biomedicine, University of Basel, Basel, Switzerland.
  • Dossena B Cytogenetics Laboratory, Ente Ospedaliero Cantonale, Bellinzona, Switzerland.
  • Rossi FM Clinical and Experimental Onco-Hematology Unit, IRCCS-Centro di Riferimento Oncologico, Aviano, Italy.
  • Zucchetto A Clinical and Experimental Onco-Hematology Unit, IRCCS-Centro di Riferimento Oncologico, Aviano, Italy.
  • Taborelli M Cytogenetics Laboratory, Ente Ospedaliero Cantonale, Bellinzona, Switzerland.
  • Gattei V Clinical and Experimental Onco-Hematology Unit, IRCCS-Centro di Riferimento Oncologico, Aviano, Italy.
  • Rossi D Università della Svizzera Italiana (USI), Institute of Oncology Research (IOR), Bellinzona, Switzerland.
  • Stathis A Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland.
  • Stussi G Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland.
  • Broggini M IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
  • Wymann MP Department of Biomedicine, University of Basel, Basel, Switzerland.
  • Wicki A Department of Oncology, University Hospital Basel, Basel, Switzerland.
  • Zucca E Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland.
  • Cmiljanovic V PIQUR Therapeutics AG, Basel, Switzerland.
  • Fabbro D PIQUR Therapeutics AG, Basel, Switzerland.
  • Bertoni F Università della Svizzera Italiana (USI), Institute of Oncology Research (IOR), Bellinzona, Switzerland. frbertoni@mac.com.
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  • 2017-10-26
Published in:
  • Clinical cancer research : an official journal of the American Association for Cancer Research. - 2018
Animals
Antineoplastic Agents
Apoptosis
Cell Line, Tumor
Cell Proliferation
Disease Models, Animal
Drug Resistance, Neoplasm
Humans
Lymphoma
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-myc
Purines
Quinazolinones
TOR Serine-Threonine Kinases
Xenograft Model Antitumor Assays
English 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.
Language
  • English
Open access status
bronze
Identifiers
Persistent URL
https://sonar.ch/global/documents/102004
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