title: The PI3K/mTOR inhibitor PF-04691502 induces apoptosis and inhibits microenvironmental signaling in CLL and the Eµ-TCL1 mouse model.
abstract: Current treatment strategies for chronic lymphocytic leukemia (CLL) involve a combination of conventional chemotherapeutics, monoclonal antibodies, and targeted signaling inhibitors. However, CLL remains largely incurable, with drug resistance and treatment relapse a common occurrence, leading to the search for novel treatments. Mechanistic target of rapamycin (mTOR)-specific inhibitors have been previously assessed but their efficacy is limited due to a positive feedback loop via mTOR complex 2 (mTORC2), resulting in activation of prosurvival signaling. In this study, we show that the dual phosphatidylinositol 3-kinase (PI3K)/mTOR inhibitor PF-04691502 does not induce an mTORC2 positive feedback loop similar to other PI3K inhibitors but does induce substantial antitumor effects. PF-04691502 significantly reduced survival coincident with the induction of Noxa and Puma, independently of immunoglobulin heavy chain variable region mutational status, CD38, and ZAP-70 expression. PF-04691502 inhibited both anti-immunoglobulin M-induced signaling and overcame stroma-induced survival signals and migratory stimuli from CXCL12. Equivalent in vitro activity was seen in the Eμ-TCL1 murine model of CLL. In vivo, PF-04691502 treatment of tumor-bearing animals resulted in a transient lymphocytosis, followed by a clear reduction in tumor in the blood, bone marrow, spleen, and lymph nodes. These data indicate that PF-04691502 or other dual PI3K/mTOR inhibitors in development may prove efficacious for the treatment of CLL, increasing our armamentarium to successfully manage this disease.
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom;
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Blunt
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom;
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Carter
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom;
authors.forename: Marta
authors.initials: M
authors.lastname: Larrayoz
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom;
authors.forename: Lindsay D
authors.initials: LD
authors.lastname: Smith
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom; Instituto Nacional de Pediatría, Cuicuilco, Mexico;
authors.forename: Maria
authors.initials: M
authors.lastname: Aguilar-Hernandez
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom;
authors.forename: Kerry L
authors.initials: KL
authors.lastname: Cox
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom;
authors.forename: Thomas
authors.initials: T
authors.lastname: Tipton
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom;
authors.forename: Mark
authors.initials: M
authors.lastname: Reynolds
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom;
authors.forename: Sarah
authors.initials: S
authors.lastname: Murphy
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom;
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Lemm
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom;
authors.forename: Samantha
authors.initials: S
authors.lastname: Dias
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom; Hematology Department, Southampton General Hospital, Southampton, United Kingdom; and.
authors.forename: Andrew
authors.initials: A
authors.lastname: Duncombe
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom;
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Strefford
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom;
authors.forename: Peter W M
authors.initials: PW
authors.lastname: Johnson
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom; Hematology Department, Southampton General Hospital, Southampton, United Kingdom; and Cancer Research United Kingdom Centre, National Institute for Health Research, Experimental Cancer Medicine Centre, University of Southampton, Southampton, United Kingdom.
authors.forename: Francesco
authors.initials: F
authors.lastname: Forconi
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom;
authors.forename: Freda K
authors.initials: FK
authors.lastname: Stevenson
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom;
authors.forename: Graham
authors.initials: G
authors.lastname: Packham
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom;
authors.forename: Mark S
authors.initials: MS
authors.lastname: Cragg
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom;
authors.forename: Andrew J
authors.identifier: http://orcid.org/0000-0003-0667-1596
authors.initials: AJ
authors.lastname: Steele
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011728:Pyridones / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: C570662:2-amino-8-(4-(2-hydroxyethoxy)cyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido(2,3-d)pyrimidin-7(8H)-one; D000970:Antineoplastic Agents; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011728:Pyridones; D011743:Pyrimidines; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases