PI3K/p110{delta} is a novel therapeutic target in multiple myeloma.
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.
Ikeda
Hiroshi
H
Lebow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Harvard Medical School, Boston, MA, USA.
Hideshima
Teru
T
Fulciniti
Mariateresa
M
Perrone
Giulia
G
Miura
Naoya
N
Yasui
Hiroshi
H
Okawa
Yutaka
Y
Kiziltepe
Tanyel
T
Santo
Loredana
L
Vallet
Sonia
S
Cristea
Diana
D
Calabrese
Elisabetta
E
Gorgun
Gullu
G
Raje
Noopur S
NS
Richardson
Paul
P
Munshi
Nikhil C
NC
Lannutti
Brian J
BJ
Puri
Kamal D
KD
Giese
Neill A
NA
Anderson
Kenneth C
KC
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
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