the phosphatidylinositol3kinase inhibitor nvpbkm120 overcomes resistance signals derived from microenvironment by regulating the aktfoxo3abim axis in chronic lymphocytic leukemia cells phosphatidylinositol3kinase pathway is constitutively activated in chronic lymphocytic leukemia mainly due to microenvironment signals including stromal cell interaction and cxcr4 and bcell receptor activation because of the importance of phosphatidylinositol3kinase signaling in chronic lymphocytic leukemia we investigated the activity of the nvpbkm120 an orally available pan class i phosphatidylinositol3kinase inhibitor sensitivity to nvpbkm120 was analyzed in chronic lymphocytic leukemia primary samples in the context of bcell receptor and microenvironment stimulation nvpbkm120 promoted mitochondrial apoptosis in most primary cells independently of common prognostic markers nvpbkm120 activity induced the blockage of phosphatidylinositol3kinase signaling decreased akt and foxo3a phosphorylation leading to concomitant mcl1 downregulation and bim induction accordingly selective knockdown of bim rescued cells from nvpbkm120induced apoptosis while the kinase inhibitor synergistically enhanced the apoptosis induced by the bh3mimetic abt263 we also found nvpbkm120 to inhibit bcell receptor and stromadependent akt pathway activation thus sensitizing chronic lymphocytic leukemia cells to bendamustine and fludarabine furthermore nvpbkm120 downregulated secretion of chemokines after bcell receptor stimulation and inhibited cell chemotaxis and actin polymerization upon cxcr4 triggering by cxcl12 our findings establish that nvpbkm120 effectively inhibits the phosphatidylinositol3kinase signaling pathway and disturbs the protective effect of the tumor microenvironment with the subsequent apoptosis induction through the aktfoxo3abim axis we provide here a strong rationale for undertaking clinical trials of nvpbkm120 in chronic lymphocytic leukemia patients alone or in combination therapies