title: PI3K/p110{delta} is a novel therapeutic target in multiple myeloma.
abstract: In this study, we demonstrate expression and examined the biologic sequelae of PI3K/p110delta signaling in multiple myeloma (MM). Knockdown of p110delta by small interfering RNA caused significant inhibition of MM cell growth. Similarly, p110delta specific small molecule inhibitor CAL-101 triggered cytotoxicity against LB and INA-6 MM cell lines and patient MM cells, associated with inhibition of Akt phosphorylation. In contrast, CAL-101 did not inhibit survival of normal peripheral blood mononuclear cells. CAL-101 overcame MM cell growth conferred by interleukin-6, insulin-like growth factor-1, and bone marrow stromal cell coculture. Interestingly, inhibition of p110delta potently induced autophagy. The in vivo inhibition of p110delta with IC488743 was evaluated in 2 murine xenograft models of human MM: SCID mice bearing human MM cells subcutaneously and the SCID-hu model, in which human MM cells are injected within a human bone chip implanted subcutaneously in SCID mice. IC488743 significantly inhibited tumor growth and prolonged host survival in both models. Finally, combined CAL-101 with bortezomib induced synergistic cytotoxicity against MM cells. Our studies therefore show that PI3K/p110delta is a novel therapeutic target in MM and provide the basis for clinical evaluation of CAL-101 to improve patient outcome in MM.
authors.affiliation: Lebow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Harvard Medical School, Boston, MA, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ikeda
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Fulciniti
authors.forename: Giulia
authors.initials: G
authors.lastname: Perrone
authors.forename: Naoya
authors.initials: N
authors.lastname: Miura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yasui
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Okawa
authors.forename: Tanyel
authors.initials: T
authors.lastname: Kiziltepe
authors.forename: Loredana
authors.initials: L
authors.lastname: Santo
authors.forename: Sonia
authors.initials: S
authors.lastname: Vallet
authors.forename: Diana
authors.initials: D
authors.lastname: Cristea
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Calabrese
authors.forename: Gullu
authors.initials: G
authors.lastname: Gorgun
authors.forename: Noopur S
authors.initials: NS
authors.lastname: Raje
authors.forename: Paul
authors.initials: P
authors.lastname: Richardson
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Lannutti
authors.forename: Kamal D
authors.initials: KD
authors.lastname: Puri
authors.forename: Neill A
authors.initials: NA
authors.lastname: Giese
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D058534:Class I Phosphatidylinositol 3-Kinases; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011687:Purines / Q000494:pharmacology*; D052999:Quinazolinones / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D013234:Stem Cells / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D015415:Biomarkers; D058534:Class I Phosphatidylinositol 3-Kinases; D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines; D052999:Quinazolinones; D034741:RNA, Small Interfering; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; C552946:idelalisib