Dual NAMPT and BTK targeting leads to synergistic killing of Waldenström macroglobulinemia cells regardless of MYD88 and CXCR4 somatic mutation status

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

Research output: Contribution to journalArticle

Abstract

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 Waldenström 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 Waldenström macroglobulinemia cells exhibit high levels of Nampt compared with normal B cells. Loss of function studies suggested a potential oncogenic role of Nampt in Waldenström macroglobulinemia cells, and BTK-inhibitor ibrutinib and FK866 resulted in a significant and synergistic anti-Waldenström 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-κB signaling, and (iv) inhibition of multiple prosurvival signaling pathways. In a murine xenograft Waldenström 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 Waldenström 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 Waldenström macroglobulinemia.

Original languageEnglish
Pages (from-to)6099-6109
Number of pages11
JournalClinical Cancer Research
Volume22
Issue number24
DOIs
Publication statusPublished - Dec 15 2016

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Nicotinamide Phosphoribosyltransferase
Waldenstrom Macroglobulinemia
Mutation
NAD
Cell Death
Survival
Growth
Drug Resistance
Heterografts
Caspase 3
Neoplasms
B-Lymphocytes
Research Design
Down-Regulation
Adenosine Triphosphate

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Dual NAMPT and BTK targeting leads to synergistic killing of Waldenström macroglobulinemia cells regardless of MYD88 and CXCR4 somatic mutation status. / 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.

In: Clinical Cancer Research, Vol. 22, No. 24, 15.12.2016, p. 6099-6109.

Research output: Contribution to journalArticle

Cea, M, Cagnetta, A, Acharya, C, Acharya, P, Tai, YT, Yang, C, Lovera, D, Soncini, D, Miglino, M, Fraternali Orcioni, G, Mastracci, L, Nencioni, A, Montecucco, F, Monacelli, F, Ballestrero, A, Hideshima, T, Chauhan, D, Gobbi, M, Lemoli, RM, Munshi, N, Treon, SP & Anderson, KC 2016, 'Dual NAMPT and BTK targeting leads to synergistic killing of Waldenström macroglobulinemia cells regardless of MYD88 and CXCR4 somatic mutation status', Clinical Cancer Research, vol. 22, no. 24, pp. 6099-6109. https://doi.org/10.1158/1078-0432.CCR-16-0630
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. / Dual NAMPT and BTK targeting leads to synergistic killing of Waldenström macroglobulinemia cells regardless of MYD88 and CXCR4 somatic mutation status. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 24. pp. 6099-6109.
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abstract = "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 Waldenstr{\"o}m 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 Waldenstr{\"o}m macroglobulinemia cells exhibit high levels of Nampt compared with normal B cells. Loss of function studies suggested a potential oncogenic role of Nampt in Waldenstr{\"o}m macroglobulinemia cells, and BTK-inhibitor ibrutinib and FK866 resulted in a significant and synergistic anti-Waldenstr{\"o}m 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-κB signaling, and (iv) inhibition of multiple prosurvival signaling pathways. In a murine xenograft Waldenstr{\"o}m 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 Waldenstr{\"o}m 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 Waldenstr{\"o}m macroglobulinemia.",
author = "Michele Cea and Antonia Cagnetta and Chirag Acharya and Prakrati Acharya and Tai, {Yu Tzu} and Cao Yang and Davide Lovera and Debora Soncini and Maurizio Miglino and {Fraternali Orcioni}, Giulio and Luca Mastracci and Alessio Nencioni and Fabrizio Montecucco and Fiammetta Monacelli and Alberto Ballestrero and Teru Hideshima and Dharminder Chauhan and Marco Gobbi and Lemoli, {Roberto M.} and Nikhil Munshi and Treon, {Steven P.} and Anderson, {Kenneth C.}",
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T1 - Dual NAMPT and BTK targeting leads to synergistic killing of Waldenström macroglobulinemia cells regardless of MYD88 and CXCR4 somatic mutation status

AU - Cea, Michele

AU - Cagnetta, Antonia

AU - Acharya, Chirag

AU - Acharya, Prakrati

AU - Tai, Yu Tzu

AU - Yang, Cao

AU - Lovera, Davide

AU - Soncini, Debora

AU - Miglino, Maurizio

AU - Fraternali Orcioni, Giulio

AU - Mastracci, Luca

AU - Nencioni, Alessio

AU - Montecucco, Fabrizio

AU - Monacelli, Fiammetta

AU - Ballestrero, Alberto

AU - Hideshima, Teru

AU - Chauhan, Dharminder

AU - Gobbi, Marco

AU - Lemoli, Roberto M.

AU - Munshi, Nikhil

AU - Treon, Steven P.

AU - Anderson, Kenneth C.

PY - 2016/12/15

Y1 - 2016/12/15

N2 - 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 Waldenström 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 Waldenström macroglobulinemia cells exhibit high levels of Nampt compared with normal B cells. Loss of function studies suggested a potential oncogenic role of Nampt in Waldenström macroglobulinemia cells, and BTK-inhibitor ibrutinib and FK866 resulted in a significant and synergistic anti-Waldenström 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-κB signaling, and (iv) inhibition of multiple prosurvival signaling pathways. In a murine xenograft Waldenström 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 Waldenström 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 Waldenström macroglobulinemia.

AB - 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 Waldenström 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 Waldenström macroglobulinemia cells exhibit high levels of Nampt compared with normal B cells. Loss of function studies suggested a potential oncogenic role of Nampt in Waldenström macroglobulinemia cells, and BTK-inhibitor ibrutinib and FK866 resulted in a significant and synergistic anti-Waldenström 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-κB signaling, and (iv) inhibition of multiple prosurvival signaling pathways. In a murine xenograft Waldenström 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 Waldenström 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 Waldenström macroglobulinemia.

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U2 - 10.1158/1078-0432.CCR-16-0630

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