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

Abstract

<b>Purpose:</b> 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 <i>in vitro</i> and <i>in vivo</i> activity and the mechanism of action of PQR309 (bimiralisib), a novel oral selective dual PI3K/mTOR inhibitor under clinical evaluation, in preclinical lymphoma models.<b>Experimental Design:</b> This study included preclinical <i>in vitro</i> activity screening on a large panel of cell lines, both as single agent and in combination, validation experiments on <i>in vivo</i> models and primary cells, proteomics and gene-expression profiling, and comparison with other signaling inhibitors.<b>Results:</b> PQR309 had <i>in vitro</i> 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.<b>Conclusions:</b> On the basis of these results, PQR309 appeared as a novel and promising compound that is worth developing in the lymphoma setting. <i>Clin Cancer Res; 24(1); 120-9. ©2017 AACR</i>.