Abstract 380: The dual PI3K/MTOR inhibitor PQR309 is active in mature B cell lymphoma cell lines bearing resistance to the PI3K-delta inhibitor idelalisib and specific gene expression features
Authors: Chiara Tarantelli , Gaudio Eugenio , Kwee Ivo , Arribas Alberto , Rinaldi Andrea , Bernasconi Elena , Cascione Luciano , Hillmann Petra , Stathis Anastasios , Carrassa Laura , Broggini Massimo , Stussi Georg , Fabbro Doriano , Zucca Emanuele , Cmiljanovic Vladimir , Bertoni Francesco 
Published: July 2016

Abstract
Introduction The PI3K-delta idelalisib is among the most promising novel agents for lymphomas, but certain patients present a primary resistant disease or relapse after an initial response. Here, we studied the dual PI3K/MTOR inhibitor PQR309 in lymphoma cell lines that were resistant to idelalisib.
Methods IC50 values were calculated with the MTT assay (72h) for 40 lymphoma cell lines. Gene expression profiling was done with Illumina HumanHT12 Expression BeadChips, data mining with Limma, GSEA and LINCSCLOUD.
Results PQR309 and idelalisib showed only a partially overlapping pattern of activity (R = 0.6). While no cell line was sensitive to idelalisib and not to PQR309, 10 cell lines were sensitive to both compounds and 7 were sensitive only to PQR309. Idelalisib median IC50 was 28 nM (95%CI; 13-147) in the PQR309/idelalisib group and 13.4 μM (7.2-16.7 μM) in the PQR309-only (P 0.0006). PQR309 median IC50 was 113 nM (33-166 nM) in PQR309/idelalisib sensitive and 193 nM (111-372 nM) in the PQR309-only sensitive cells (P 0.03). No differences between the two groups were observed in terms of histology, diffuse large B cell lymphoma cell of origin, MYC deregulation, TP53 inactivation, BCL6 or BCL2 translocations. The gene expression signature of the PQR309/idelalisib sensitive cell lines was enriched of genes involved in IFN signaling, IL6/Jak/Stat3 signaling, oxidative phosphorylation, PI3K/MTOR signaling, chemokines signaling and proteasome (GSEA FDR &lt;0.05; core enrichment genes including among others: PIK3CD, PTPN6, CCL3, CXCR4, CXCL10, JAK2, MYD88, STAT3, BAX, CDKN1A, AKT1, CDK2, PRKCB, PSMC4, PSMC2, MX1, MX2). Conversely, gene expression profiles of the PQR309-only sensitive cell lines were enriched of genes involved in hypoxia, IL2/STAT5 and glycolysis (GSEA FDR &lt;0.05; core enrichment genes including, among others, ENO2, AKAP12, PRKCA, VEGFA, XBP1). The gene expression signature derived from genetic silencing of SOX4 in different cancer cells overlapped with the differences observed between our groups (connectivity score = -0.5) and the transcription factor itself, a positive-regulator of the PI3K/AKT pathway, was more expressed in the PQR309-only cells (log ratio 0.99 P 0.036). The cell surface marker CD24, involved in PI3K signaling, was the most up-regulated gene in the PQR309/idelalisib sensitive group (log ratio -2.1 P 0.02). Transcripts more expressed in the PQR309-only sensitive cells overlapped with genes down-regulated by PI3K and MTOR inhibitors in cancer cell lines (connectivity scores &lt; -0.55).
Conclusions. The dual PI3K/MTOR inhibitor PQR309 was active in a subset of mature B cell lymphoma cell lines bearing a primary resistance to the PI3K-delta inhibitor idelalisib and specific gene expression features. Expression of SOX4 and CD24 appear worth of validation on clinical specimens derived from prospectively treated patients.
Citation Format: Tarantelli Chiara, Eugenio Gaudio, Ivo Kwee, Alberto Arribas, Andrea Rinaldi, Elena Bernasconi, Luciano Cascione, Petra Hillmann, Anastasios Stathis, Laura Carrassa, Massimo Broggini, Georg Stussi, Doriano Fabbro, Emanuele Zucca, Vladimir Cmiljanovic, Francesco Bertoni. The dual PI3K/MTOR inhibitor PQR309 is active in mature B cell lymphoma cell lines bearing resistance to the PI3K-delta inhibitor idelalisib and specific gene expression features. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 380.