PI3K/p110δ is a novel therapeutic target in multiple myeloma

Hiroshi Ikeda, Teru Hideshima, Mariateresa Fulciniti, Giulia Perrone, Naoya Miura, Hiroshi Yasui, Yutaka Okawa, Tanyel Kiziltepe, Loredana Santo, Sonia Vallet, Diana Cristea, Elisabetta Calabrese, Gullu Gorgun, Noopur S. Raje, Paul Richardson, Nikhil C. Munshi, Brian J. Lannutti, Kamal D. Puri, Neill A. Giese, Kenneth C. Anderson

Research output: Contribution to journalArticlepeer-review

146 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1460-1468
Number of pages9
JournalBlood
Volume116
Issue number9
DOIs
StatePublished - Sep 2 2010

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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