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

Purpose: Activation of the PI3K/mTOR signaling pathway is recurrent in different lymphoma types and pharmacological 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 anti-lymphoma 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 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 of other signaling inhibitors largely overlapped. PQR309 showed activity in cells with primary or secondary resistance to idelalisib. Conclusions: Based on these results, PQR309 appeared as a novel and promising compound being worthwhile developing in the lymphoma setting.

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