PI3K/p110δ is a novel therapeutic target in multiple myeloma

• Published in: Blood 2010-09, Vol.116 (9), p.1460-1468
• Main Authors: Ikeda, Hiroshi, Hideshima, Teru, Fulciniti, Mariateresa, Perrone, Giulia, Miura, Naoya, Yasui, Hiroshi, Okawa, Yutaka, Kiziltepe, Tanyel, Santo, Loredana, Vallet, Sonia, Cristea, Diana, Calabrese, Elisabetta, Gorgun, Gullu, Raje, Noopur S., Richardson, Paul, Munshi, Nikhil C., Lannutti, Brian J., Puri, Kamal D., Giese, Neill A., Anderson, Kenneth C.
• Format: Article
• Language: English
• Subjects: Lymphoid Neoplasia
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2009-06-222943

In this study, we demonstrate expression and examined the biologic sequelae of PI3K/p110δ signaling in multiple myeloma (MM). Knockdown of p110δ by small interfering RNA caused significant inhibition of MM cell growth. Similarly, p110δ 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 p110δ potently induced autophagy. The in vivo inhibition of p110δ 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/p110δ is a novel therapeutic target in MM and provide the basis for clinical evaluation of CAL-101 to improve patient outcome in MM.