Effects of the novel PI3K d/? inhibitor RP6530 on global gene expression in Hodgkin Lymphoma cell lines.

Tumor-associated macrophages (TAMs) are involved in the pathogenesis of Hodgkin lymphoma (HL) and correlate with negative prognosis. The phosphatidylinositol 3-kinase (PI3K) mediates tumor and endothelial cell survival, and macrophage activation. As PI3Kd and PI3K? are constitutively activated in HL, we describe RP6530, a novel PI3Kd/? inhibitor, in clinical development for HL and NHL. RP6530 exhibits anti-proliferative and cytotoxic activity both in vitro in HL cell lines and in vivo in HL xenograft mouse models. By inhibiting the metabolic regulator Pyruvate Kinase M2 (PKM2), RP6530 downregulates lactic acid metabolism in HL cells switching the activation of macrophages from an immunosuppressive M2-like phenotype to a more inflammatory M1-like state. RP6530 reshapes the tumor microenvironment (TME), through the re-polarization of TAMs into pro-inflammatory macrophages and the inhibition of tumor vasculature. These data demonstrate the central role of PI3K d/? inhibition for targeting HL cells and TME, indicating RP6530 as a novel therapeutic opportunity for HL patients. Overall design: Profiling of the transcriptome of L-540 and KM-H2 Hodgkin lymphoma cell lines after in vitro treatment with the novel PI3Kd/? inhibitor RP6530 (100nM and 10uM) for 6 hours and RP6530 (10uM) for 24 hours and subjected to polyA-RNA sequencing using Illumina platform. Two biological replicates were profiled for each cell type and time point.