Targeting p38 or MK2 Enhances the Anti-Leukemic Activity of Smac-Mimetics

Najoua Lalaoui, Kay Hanggi, Gabriela Brumatti, Diep Chau, Nhu-Y N Nguyen, Lazaros Vasilikos, Lisanne M Spilgies, Denise A Heckmann, Chunyan Ma, Margherita Ghisi, Jessica M Salmon, Geoffrey M Matthews, Elisha de Valle, Donia M Moujalled, Manoj B Menon, Sukhdeep Kaur Spall, Stefan P Glaser, Jennifer Richmond, Richard B Lock, Stephen M Condon & 10 others Raffi Gugasyan, Matthias Gaestel, Mark Guthridge, Ricky W Johnstone, Lenka Munoz, Andrew Wei, Paul G Ekert, David L Vaux, W. Wei-Lynn Wong, John Silke

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Birinapant is a smac-mimetic (SM) in clinical trials for treating cancer. SM antagonize inhibitor of apoptosis (IAP) proteins and simultaneously induce tumor necrosis factor (TNF) secretion to render cancers sensitive to TNF-induced killing. To enhance SM efficacy, we screened kinase inhibitors for their ability to increase TNF production of SM-treated cells. We showed that p38 inhibitors increased TNF induced by SM. Unexpectedly, even though p38 is required for Toll-like receptors to induce TNF, loss of p38 or its downstream kinase MK2 increased induction of TNF by SM. Hence, we show that the p38/MK2 axis can inhibit or promote TNF production, depending on the stimulus. Importantly, clinical p38 inhibitors overcame resistance of primary acute myeloid leukemia to birinapant. Lalaoui et al. show that inhibition of p38 or its downstream kinase MK2, in contrast to reducing Toll-like receptor-mediated tumor necrosis factor (TNF) production, increases TNF production upon smac-mimetic (SM) treatment and enhances the anti-tumor efficacy of SM.
Original languageEnglish
Pages (from-to)145 - 158
Number of pages14
JournalCancer Cell
Volume29
Issue number2
DOIs
Publication statusPublished - 2016

Cite this

Lalaoui, N., Hanggi, K., Brumatti, G., Chau, D., Nguyen, N-Y. N., Vasilikos, L., ... Silke, J. (2016). Targeting p38 or MK2 Enhances the Anti-Leukemic Activity of Smac-Mimetics. Cancer Cell, 29(2), 145 - 158. https://doi.org/10.1016/j.ccell.2016.01.006
Lalaoui, Najoua ; Hanggi, Kay ; Brumatti, Gabriela ; Chau, Diep ; Nguyen, Nhu-Y N ; Vasilikos, Lazaros ; Spilgies, Lisanne M ; Heckmann, Denise A ; Ma, Chunyan ; Ghisi, Margherita ; Salmon, Jessica M ; Matthews, Geoffrey M ; de Valle, Elisha ; Moujalled, Donia M ; Menon, Manoj B ; Spall, Sukhdeep Kaur ; Glaser, Stefan P ; Richmond, Jennifer ; Lock, Richard B ; Condon, Stephen M ; Gugasyan, Raffi ; Gaestel, Matthias ; Guthridge, Mark ; Johnstone, Ricky W ; Munoz, Lenka ; Wei, Andrew ; Ekert, Paul G ; Vaux, David L ; Wong, W. Wei-Lynn ; Silke, John. / Targeting p38 or MK2 Enhances the Anti-Leukemic Activity of Smac-Mimetics. In: Cancer Cell. 2016 ; Vol. 29, No. 2. pp. 145 - 158.
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title = "Targeting p38 or MK2 Enhances the Anti-Leukemic Activity of Smac-Mimetics",
abstract = "Birinapant is a smac-mimetic (SM) in clinical trials for treating cancer. SM antagonize inhibitor of apoptosis (IAP) proteins and simultaneously induce tumor necrosis factor (TNF) secretion to render cancers sensitive to TNF-induced killing. To enhance SM efficacy, we screened kinase inhibitors for their ability to increase TNF production of SM-treated cells. We showed that p38 inhibitors increased TNF induced by SM. Unexpectedly, even though p38 is required for Toll-like receptors to induce TNF, loss of p38 or its downstream kinase MK2 increased induction of TNF by SM. Hence, we show that the p38/MK2 axis can inhibit or promote TNF production, depending on the stimulus. Importantly, clinical p38 inhibitors overcame resistance of primary acute myeloid leukemia to birinapant. Lalaoui et al. show that inhibition of p38 or its downstream kinase MK2, in contrast to reducing Toll-like receptor-mediated tumor necrosis factor (TNF) production, increases TNF production upon smac-mimetic (SM) treatment and enhances the anti-tumor efficacy of SM.",
author = "Najoua Lalaoui and Kay Hanggi and Gabriela Brumatti and Diep Chau and Nguyen, {Nhu-Y N} and Lazaros Vasilikos and Spilgies, {Lisanne M} and Heckmann, {Denise A} and Chunyan Ma and Margherita Ghisi and Salmon, {Jessica M} and Matthews, {Geoffrey M} and {de Valle}, Elisha and Moujalled, {Donia M} and Menon, {Manoj B} and Spall, {Sukhdeep Kaur} and Glaser, {Stefan P} and Jennifer Richmond and Lock, {Richard B} and Condon, {Stephen M} and Raffi Gugasyan and Matthias Gaestel and Mark Guthridge and Johnstone, {Ricky W} and Lenka Munoz and Andrew Wei and Ekert, {Paul G} and Vaux, {David L} and Wong, {W. Wei-Lynn} and John Silke",
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Lalaoui, N, Hanggi, K, Brumatti, G, Chau, D, Nguyen, N-YN, Vasilikos, L, Spilgies, LM, Heckmann, DA, Ma, C, Ghisi, M, Salmon, JM, Matthews, GM, de Valle, E, Moujalled, DM, Menon, MB, Spall, SK, Glaser, SP, Richmond, J, Lock, RB, Condon, SM, Gugasyan, R, Gaestel, M, Guthridge, M, Johnstone, RW, Munoz, L, Wei, A, Ekert, PG, Vaux, DL, Wong, WW-L & Silke, J 2016, 'Targeting p38 or MK2 Enhances the Anti-Leukemic Activity of Smac-Mimetics', Cancer Cell, vol. 29, no. 2, pp. 145 - 158. https://doi.org/10.1016/j.ccell.2016.01.006

Targeting p38 or MK2 Enhances the Anti-Leukemic Activity of Smac-Mimetics. / Lalaoui, Najoua; Hanggi, Kay; Brumatti, Gabriela; Chau, Diep; Nguyen, Nhu-Y N; Vasilikos, Lazaros; Spilgies, Lisanne M; Heckmann, Denise A; Ma, Chunyan; Ghisi, Margherita; Salmon, Jessica M; Matthews, Geoffrey M; de Valle, Elisha; Moujalled, Donia M; Menon, Manoj B; Spall, Sukhdeep Kaur; Glaser, Stefan P; Richmond, Jennifer; Lock, Richard B; Condon, Stephen M; Gugasyan, Raffi; Gaestel, Matthias; Guthridge, Mark; Johnstone, Ricky W; Munoz, Lenka; Wei, Andrew; Ekert, Paul G; Vaux, David L; Wong, W. Wei-Lynn; Silke, John.

In: Cancer Cell, Vol. 29, No. 2, 2016, p. 145 - 158.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Targeting p38 or MK2 Enhances the Anti-Leukemic Activity of Smac-Mimetics

AU - Lalaoui, Najoua

AU - Hanggi, Kay

AU - Brumatti, Gabriela

AU - Chau, Diep

AU - Nguyen, Nhu-Y N

AU - Vasilikos, Lazaros

AU - Spilgies, Lisanne M

AU - Heckmann, Denise A

AU - Ma, Chunyan

AU - Ghisi, Margherita

AU - Salmon, Jessica M

AU - Matthews, Geoffrey M

AU - de Valle, Elisha

AU - Moujalled, Donia M

AU - Menon, Manoj B

AU - Spall, Sukhdeep Kaur

AU - Glaser, Stefan P

AU - Richmond, Jennifer

AU - Lock, Richard B

AU - Condon, Stephen M

AU - Gugasyan, Raffi

AU - Gaestel, Matthias

AU - Guthridge, Mark

AU - Johnstone, Ricky W

AU - Munoz, Lenka

AU - Wei, Andrew

AU - Ekert, Paul G

AU - Vaux, David L

AU - Wong, W. Wei-Lynn

AU - Silke, John

PY - 2016

Y1 - 2016

N2 - Birinapant is a smac-mimetic (SM) in clinical trials for treating cancer. SM antagonize inhibitor of apoptosis (IAP) proteins and simultaneously induce tumor necrosis factor (TNF) secretion to render cancers sensitive to TNF-induced killing. To enhance SM efficacy, we screened kinase inhibitors for their ability to increase TNF production of SM-treated cells. We showed that p38 inhibitors increased TNF induced by SM. Unexpectedly, even though p38 is required for Toll-like receptors to induce TNF, loss of p38 or its downstream kinase MK2 increased induction of TNF by SM. Hence, we show that the p38/MK2 axis can inhibit or promote TNF production, depending on the stimulus. Importantly, clinical p38 inhibitors overcame resistance of primary acute myeloid leukemia to birinapant. Lalaoui et al. show that inhibition of p38 or its downstream kinase MK2, in contrast to reducing Toll-like receptor-mediated tumor necrosis factor (TNF) production, increases TNF production upon smac-mimetic (SM) treatment and enhances the anti-tumor efficacy of SM.

AB - Birinapant is a smac-mimetic (SM) in clinical trials for treating cancer. SM antagonize inhibitor of apoptosis (IAP) proteins and simultaneously induce tumor necrosis factor (TNF) secretion to render cancers sensitive to TNF-induced killing. To enhance SM efficacy, we screened kinase inhibitors for their ability to increase TNF production of SM-treated cells. We showed that p38 inhibitors increased TNF induced by SM. Unexpectedly, even though p38 is required for Toll-like receptors to induce TNF, loss of p38 or its downstream kinase MK2 increased induction of TNF by SM. Hence, we show that the p38/MK2 axis can inhibit or promote TNF production, depending on the stimulus. Importantly, clinical p38 inhibitors overcame resistance of primary acute myeloid leukemia to birinapant. Lalaoui et al. show that inhibition of p38 or its downstream kinase MK2, in contrast to reducing Toll-like receptor-mediated tumor necrosis factor (TNF) production, increases TNF production upon smac-mimetic (SM) treatment and enhances the anti-tumor efficacy of SM.

UR - http://www.sciencedirect.com/science/article/pii/S1535610816000350

U2 - 10.1016/j.ccell.2016.01.006

DO - 10.1016/j.ccell.2016.01.006

M3 - Article

VL - 29

SP - 145

EP - 158

JO - Cancer Cell

JF - Cancer Cell

SN - 1535-6108

IS - 2

ER -

Lalaoui N, Hanggi K, Brumatti G, Chau D, Nguyen N-YN, Vasilikos L et al. Targeting p38 or MK2 Enhances the Anti-Leukemic Activity of Smac-Mimetics. Cancer Cell. 2016;29(2):145 - 158. https://doi.org/10.1016/j.ccell.2016.01.006