title: The phosphatidylinositol-3-kinase inhibitor NVP-BKM120 overcomes resistance signals derived from microenvironment by regulating the Akt/FoxO3a/Bim axis in chronic lymphocytic leukemia cells.
abstract: Phosphatidylinositol-3-kinase pathway is constitutively activated in chronic lymphocytic leukemia mainly due to microenvironment signals, including stromal cell interaction and CXCR4 and B-cell receptor activation. Because of the importance of phosphatidylinositol-3-kinase signaling in chronic lymphocytic leukemia, we investigated the activity of the NVP-BKM120, an orally available pan class I phosphatidylinositol-3-kinase inhibitor. Sensitivity to NVP-BKM120 was analyzed in chronic lymphocytic leukemia primary samples in the context of B-cell receptor and microenvironment stimulation. NVP-BKM120 promoted mitochondrial apoptosis in most primary cells independently of common prognostic markers. NVP-BKM120 activity induced the blockage of phosphatidylinositol-3-kinase signaling, decreased Akt and FoxO3a phosphorylation leading to concomitant Mcl-1 downregulation and Bim induction. Accordingly, selective knockdown of BIM rescued cells from NVP-BKM120-induced apoptosis, while the kinase inhibitor synergistically enhanced the apoptosis induced by the BH3-mimetic ABT-263. We also found NVP-BKM120 to inhibit B-cell receptor- and stroma-dependent Akt pathway activation, thus sensitizing chronic lymphocytic leukemia cells to bendamustine and fludarabine. Furthermore, NVP-BKM120 down-regulated secretion of chemokines after B-cell receptor stimulation and inhibited cell chemotaxis and actin polymerization upon CXCR4 triggering by CXCL12. Our findings establish that NVP-BKM120 effectively inhibits the phosphatidylinositol-3-kinase signaling pathway and disturbs the protective effect of the tumor microenvironment with the subsequent apoptosis induction through the Akt/FoxO3a/Bim axis. We provide here a strong rationale for undertaking clinical trials of NVP-BKM120 in chronic lymphocytic leukemia patients alone or in combination therapies.
authors.affiliation: dcolomer@clinic.ub.es.
authors.forename: Laia
authors.initials: L
authors.lastname: Rosich
authors.forename: Ifigènia
authors.initials: I
authors.lastname: Saborit-Villarroya
authors.forename: Mónica
authors.initials: M
authors.lastname: López-Guerra
authors.forename: Sílvia
authors.initials: S
authors.lastname: Xargay-Torrent
authors.forename: Arnau
authors.initials: A
authors.lastname: Montraveta
authors.forename: Marta
authors.initials: M
authors.lastname: Aymerich
authors.forename: Neus
authors.initials: N
authors.lastname: Villamor
authors.forename: Elias
authors.initials: E
authors.lastname: Campo
authors.forename: Patricia
authors.initials: P
authors.lastname: Pérez-Galán
authors.forename: Gaël
authors.initials: G
authors.lastname: Roué
authors.forename: Dolors
authors.initials: D
authors.lastname: Colomer
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000631:Aminopyridines / Q000494:pharmacology* / Q000627:therapeutic use; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D000072224:Bcl-2-Like Protein 11; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D018920:Coculture Techniques; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000502:physiology*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000502:physiology*; D008875:Middle Aged; D009025:Morpholines / Q000494:pharmacology* / Q000627:therapeutic use; D051058:Oncogene Protein v-akt / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D059016:Tumor Microenvironment / Q000187:drug effects / Q000502:physiology*
chemical_list: D000631:Aminopyridines; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D008565:Membrane Proteins; D009025:Morpholines; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins; C000606775:BCL2L11 protein, human; C499517:FOXO3 protein, human; C571178:NVP-BKM120