Dual NAMPT and BTK Targeting Leads to Synergistic Killing of Waldenstrom Macroglobulinemia Cells Regardless of MYD88 and CXCR4 Somatic Mutation Status

作者：Cea Michele; Cagnetta Antonia; Acharya Chirag; Acharya Prakrati; Tai Yu Tzu; Yang Cao; Lovera Davide; Soncini Debora; Miglino Maurizio; Fraternali Orcioni Giulio; Mastracci Luca; Nencioni Alessio; Montecucco Fabrizio; Monacelli Fiammetta; Ballestrero Alberto; Hideshima Teru; Chauhan Dharminder; Gobbi Marco; Lemoli Roberto M; Munshi Nikhil; Treon Steven P; Anderson Kenneth C

来源：Clinical Cancer Research, 2016, 22(24): 6099-6109.

DOI：10.1158/1078-0432.CCR-16-0630

Purpose: Nicotinamide phosphoribosyltransferase (Nampt) regulates intracellular NAD(+) pool and is highly expressed in a number of malignancies. FK866, a selective inhibitor of Nampt, depletes intracellular NAD(+) levels, thereby blocking cellular metabolism and triggering sensitization to other drugs and cell death. Here we characterized the antitumor effects of Nampt inhibition in Waldenstrom macroglobulinemia.
Experimental Design: We investigated Nampt role in MW cells using both mRNA and protein expression analyses. We have also used loss-of-function approaches to investigate the growth and survival effects of Nampt on MW cells and further tested the anti-MW activity of dual Nampt and BTK inhibition in vitro and in vivo.
Results: We found that Waldenstrom macroglobulinemia cells exhibit high levels of Nampt compared with normal B cells. Loss of function studies suggested a potential oncogenic role of Nampt in Waldenstrom macroglobulinemia cells, and BTK-inhibitor ibrutinib and FK866 resulted in a significant and synergistic anti-Waldenstrom macroglobulinemia cell death, regardless of MYD88 and CXCR4 mutational status. Cell death was associated with: (i) activation of caspase-3, PARP and downregulation of Mcl-1, (ii) enhanced intracellular ATP and NAD(+) depletion, (iii) inhibition of NF-kappa B signaling, and (iv) inhibition of multiple prosurvival signaling pathways. In a murine xenograft Waldenstrom macroglobulinemia model, low-dose combination FK866 and ibrutinib is well tolerated, significantly inhibits tumor growth, and prolongs host survival.
Conclusions: Our results show intracellular NAD(+) level as crucial for proliferation and survival of Waldenstrom macroglobulinemia cells, and provides the mechanistic preclinical rationale for targeting Nampt, either alone or with Ibrutinib, to overcome drug resistance and improve patient outcome in Waldenstrom macroglobulinemia.

• 出版日期2016-12-15
• 单位中国地震局