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

Abstract

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 and activity and the mechanism of action of PQR309 (bimiralisib), a novel oral selective dual PI3K/mTOR inhibitor under clinical evaluation, in preclinical lymphoma models. This study included preclinical activity screening on a large panel of cell lines, both as single agent and in combination, validation experiments on models and primary cells, proteomics and gene-expression profiling, and comparison with other signaling inhibitors. PQR309 had 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. On the basis of these results, PQR309 appeared as a novel and promising compound that is worth developing in the lymphoma setting. .

Single and combined BTK and PI3Kδ inhibition with acalabrutinib and ACP‐319 in pre‐clinical models of aggressive lymphomas

“…In particular, the cell lines derived from MCL and ABC DLBCL presented reduction of p‐AKT and increased cytotoxicity. The benefit of the combination observed in our lymphoma models is in agreement with that observed in CLL models using the same compounds (Niemann et al , ), and also supported by data obtained using different BTK and PI3K inhibitors (Mathews Griner et al , ; Paul et al , ; Yahiaoui et al , ; Faia et al , ; Schaffer et al , ; Tarantelli et al , ; Tarantelli et al , ). Both sets of data support an on‐going clinical study (NCT02328014), which has shown positive signals of activity, especially in ABC DLBCL (Barr et al , ).…”

“…Both sets of data support an on‐going clinical study (NCT02328014), which has shown positive signals of activity, especially in ABC DLBCL (Barr et al , ). Both PI3Kδ and BTK inhibitors target BCR signalling but via different modalities (de Rooij et al , ; Tarantelli et al , ), thus, when given together, they are expected to achieve a better inhibition of the pathway and prevent adaptive mechanisms (de Rooij et al , ). The feasibility of this type combination is indicated by the very recently reported results of a phase 1‐1b trial that combined ibrutinib with the PI3Kδ inhibitor umbralisib (TGR‐1202) for patients with relapsed/refractory CLL (Davids et al , ).…”

“…The effect on cell proliferation, cell cycle analysis and protein extraction, separation and immunoblotting were determined as previously described (Mensah et al , ; Tarantelli et al , ). The following antibodies were used: ERK (catalogue number 93; Santa Cruz Biotechnology, Santa Cruz, CA, USA), phosphorylated (P‐)ERK (7383; Santa Cruz Biotechnology), AKT (9272;Cell Signaling Technology [CST], Leiden, the Netherlands), p‐AKT (Ser 473) (4060; CST); BTK (8547; CST), p‐BTK (Tyr 223) (87141; CST), IRF4 (4299; CST), anti‐GAPDH (FF26A; Ebioscence, Thermo Fisher Scientific, Waltham, MA, USA) and anti‐vinculin (V9131; Sigma Aldrich Chemie GmbH, Buchs, Switzerland).…”

DNA Damage Response Inhibitor Combinations Exert Synergistic Antitumor Activity in Aggressive B-Cell Lymphomas

“…Cell lines derived from mature B-cell lymphomas were used, as specified previously (9,20). Cell lines had been authenticated by the authors in the last 6 months.…”

In vitro demonstration of synergism with pixantrone combined with targeted agents in lymphomas

“…We then evaluated the combination of pixantrone with different anti‐lymphoma compounds in preclinical models of DLBCL and T‐cell lymphoma exposed to the single agent or the combination for 72 h, as previously described (Tarantelli et al , ). Synergism was defined in the presence of a Chou‐Talalay Combination Index (CI) between 0·3 and 0·9, additivity for CI between 0·9 and 1·1, and antagonism/no benefit for CI > 1·1 (Tarantelli et al , ) (Figure , Table SIV). The combination with the phosphoinositide‐3 kinase‐delta inhibitor idelalisib was beneficial in all the 12 (100%) DLBCL cell lines studied.…”