PQR309 is a novel dual PI3K/mTOR inhibitor with preclinical antitumor activity in lymphomas as a single agent and in combination therapy

Chiara Tarantelli, Eugenio Gaudio, Alberto J. Arribas, Ivo Kwee, Petra Hillmann, Andrea Rinaldi, Luciano Cascione, Filippo Spriano, Elena Bernasconi, Francesca Guidetti, Laura Carrassa, Roberta Bordone Pittau, Florent Beaufils, Reto Ritschard, Denise Rageot, Alexander Sele, Barbara Dossena, Francesca Maria Rossi, Antonella Zucchetto, Monica TaborelliValter Gattei, Davide Rossi, Anastasios Stathis, Georg Stussi, Massimo Broggini, Matthias P. Wymann, Andreas Wicki, Emanuele Zucca, Vladimir Cmiljanovic, Doriano Fabbro, Francesco Bertoni

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)120-129
Number of pages10
JournalClinical Cancer Research
Volume24
Issue number1
DOIs
Publication statusPublished - Jan 1 2018

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Tarantelli, C., Gaudio, E., Arribas, A. J., Kwee, I., Hillmann, P., Rinaldi, A., Cascione, L., Spriano, F., Bernasconi, E., Guidetti, F., Carrassa, L., Pittau, R. B., Beaufils, F., Ritschard, R., Rageot, D., Sele, A., Dossena, B., Rossi, F. M., Zucchetto, A., ... Bertoni, F. (2018). PQR309 is a novel dual PI3K/mTOR inhibitor with preclinical antitumor activity in lymphomas as a single agent and in combination therapy. Clinical Cancer Research, 24(1), 120-129. https://doi.org/10.1158/1078-0432.CCR-17-1041