title: Dual PI3K/mTOR inhibition is required to effectively impair microenvironment survival signals in mantle cell lymphoma.
abstract: Phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway activation contributes to mantle cell lymphoma (MCL) pathogenesis and drug resistance. Antitumor activity has been observed with mTOR inhibitors. However, they have shown limited clinical efficacy in relation to drug activation of feedback loops. Selective PI3K inhibition or dual PI3K/mTOR catalytic inhibition are different therapeutic approaches developed to achieve effective pathway blockage. Here, we have performed a comparative analysis of the mTOR inhibitor everolimus, the pan-PI3K inhibitor NVP-BKM120 and the dual PI3K/mTOR inhibitor NVP-BEZ235 in primary MCL cells. We found NVP-BEZ235 to be more powerful than everolimus or NVP-BKM120 in PI3K/Akt/mTOR signaling inhibition, indicating that targeting the PI3K/Akt/mTOR pathway at multiple levels is likely to be a more effective strategy for the treatment of MCL than single inhibition of these kinases. Among the three drugs, NVP-BEZ235 induced the highest change in gene expression profile. Functional validation demonstrated that NVP-BEZ235 inhibited angiogenesis, migration and tumor invasiveness in MCL cells. NVP-BEZ235 was the only drug able to block IL4 and IL6/STAT3 signaling which compromise the therapeutic effect of chemotherapy in MCL. Our findings support the use of the dual PI3K/mTOR inhibitor NVP-BEZ235 as a promising approach to interfere with the microenvironment-related processes in MCL.
authors.affiliation: Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Rosich
authors.affiliation: Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Arnau
authors.initials: A
authors.lastname: Montraveta
authors.affiliation: Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Xargay-Torrent
authors.affiliation: Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: López-Guerra
authors.affiliation: Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Jocabed
authors.initials: J
authors.lastname: Roldán
authors.affiliation: Hematopathology Unit, Department of Pathology, Hospital Clínic, Barcelona, Spain. IDIBAPS, University of Barcelona, Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Aymerich
authors.affiliation: IDIBAPS, University of Barcelona, Barcelona, Spain.
authors.forename: Itziar
authors.initials: I
authors.lastname: Salaverria
authors.affiliation: IDIBAPS, University of Barcelona, Barcelona, Spain.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Beà
authors.affiliation: Hematopathology Unit, Department of Pathology, Hospital Clínic, Barcelona, Spain. IDIBAPS, University of Barcelona, Barcelona, Spain.
authors.forename: Elías
authors.initials: E
authors.lastname: Campo
authors.affiliation: Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Pérez-Galán
authors.affiliation: Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Gaël
authors.initials: G
authors.lastname: Roué
authors.affiliation: Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. Hematopathology Unit, Department of Pathology, Hospital Clínic, Barcelona, Spain.
authors.forename: Dolors
authors.initials: D
authors.lastname: Colomer
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000378:metabolism; D000068338:Everolimus; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D059467:Transcriptome; D059016:Tumor Microenvironment / Q000187:drug effects; D000093242:Interleukin-6 Inhibitors
chemical_list: D000631:Aminopyridines; D054377:Chemokine CXCL12; D000068338:Everolimus; D007093:Imidazoles; D015847:Interleukin-4; D015850:Interleukin-6; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D000093242:Interleukin-6 Inhibitors; C515255:CXCL12 protein, human; C508598:IL4 protein, human; C508600:IL6 protein, human; C571178:NVP-BKM120; C546842:MTOR protein, human; C531198:dactolisib