Abstract B041: PQR309-containing combinations show synergistic antilymphoma activity
Authors: Tarantelli Chiara , Bernasconi Elena , Spriano Filippo , Hillmann Petra , Gaudio Eugenio , Cascione Luciano , Kwee Ivo , Fabbro Doriano , Zucca Emanuele , Cmiljanovic Vladimir , Bertoni Francesco 
Published: August 2018

Abstract
Background: The PI3K/AKT/mTOR pathway represents an important therapeutic target in lymphomas. PQR309 is a dual PI3K/mTOR inhibitor under clinical investigation for patients affected by lymphomas and solid tumors. Here, we present novel data obtained with PQR309 in combination with other targeted agents in lymphoma models. Materials and Methods: Established lymphoma cell lines derived from mantle cell lymphoma (MCL) and from diffuse large B cell lymphoma (DLBCL) of the activated B cell like (ABC) or the germinal center B cell type (GCB) were exposed to combinations of PQR309 with selected compounds for 72 hrs. Synergy was assessed with Chou-Talalay combination index (CI): synergism (&lt;0.9), additive (0.9-1.1), antagonism/no benefit (&gt; 1.1). Results: PQR309 was evaluated in combination with additional targeted agents. The combination with the BTK inhibitor ibrutinib was synergistic in 3/3 ABC-DLBCL (HBL1, median CI 0.26, 95%C.I. 0.22-0.29; OCI-LY-10, median CI 0.67, 95%C.I. 0.43-0.75; OCI-LY-3, median CI 0.68, 95%C.I. 0.6-0.73) and in 4/4 MCL (JEKO1, median CI 0.53, 95%C.I. 0.47-0.64; REC1, median CI 0.6, 95%C.I. 0.37-0.69; SP49, median CI 0.68, 95%C.I. 0.55-0.81; UPN1, median CI 0.69, 95%C.I. 0.64-0.75) cell lines tested. When PQR309 was assayed in combination with the BCL2 inhibitor venetoclax in MCL, 3/4 were synergistic (JEKO1, median CI 0.82, 95% CI 0.75-1.01; REC1, median CI 0.49, 95% CI 0.35-0.78; SP49, median CI 0.8, 95% CI 0.67-0.93) while one had no benefit (UPN1, CI &gt;3). The combination with the novel anti-BRD4 Protac ARV-825 was synergistic in 4/8 cell lines (RI1, median CI 0.61, 95% CI 0.51-0.66; KARPAS422, median CI 0.68, 95% CI 0.56-0.81; OCI-LY-18, median CI 0.78, 95% CI 0.71-1.04; SU-DHL-6, median CI 0.71, 95% CI 0.65-0.88), additive in 2/8 (U2932, median CI 0.98, 95% CI 0.9-1.14; DOHH2, median CI 0.97, 95% CI 0.67-1.09) and with no benefit in 2/8 (OCI-LY-3, median CI 1.29, 95% CI 1.02-1.39; TMD8, median CI 1.35, 95% CI 1.33-1.4) cell lines. Finally, following the previous demonstration of an upregulation of PIM1 kinase after exposure to PQR309 and synergism combining PQR309 with the PIM inhibitor AZD1208 in a few DLBCL cell lines (Tarantelli et al, ASH 2015), we tested the efficacy of this combination in a larger panel of DLBCL cell lines. Seven out of seven DLBCL lymphoma cell lines benefited from the combination, achieving synergism to PQR309 plus AZD1208 (OCI-LY-10, median CI 0.51, 95% CI 0.47-0.57; OCI-LY-3, median CI 0.52, 95% CI 0.49-0.66; RI1, median CI 0.2, 95% CI 0.16-0.22; U2932, median CI 0.37, 95% CI 0.34-0.44; DOHH2, median CI 0.34, 95% CI 0.31-0.41; KARPAS422, median CI 0.86, 95% CI 0.8-0.92; OCI-LY-18, median CI 0.54, 95% CI 0.46-0.66). Conclusions: PQR309 showed synergistic activity in B cell lymphomas when combined with inhibitors of BTK, BCL2, BRD4, and PIM, suggesting these combinations are worthy of being further investigated.
Citation Format: Chiara Tarantelli, Elena Bernasconi, Filippo Spriano, Petra Hillmann, Eugenio Gaudio, Luciano Cascione, Ivo Kwee, Doriano Fabbro, Emanuele Zucca, Vladimir Cmiljanovic, Francesco Bertoni. PQR309-containing combinations show synergistic antilymphoma activity [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B041.