Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia

Luis A. Carvajal, Daniela Ben Neriah, Adrien Senecal, Lumie Benard, Victor Thiruthuvanathan, Tatyana Yatsenko, Swathi-Rao Narayanagari, Justin C. Wheat, Tihomira I. Todorova, Kelly Mitchell, Charles Kenworthy, Vincent Guerlavais, D. Allen Annis, Boris A. Bartholdy, Britta Will, Jesus D. Anampa Mesias, Ioannis Mantzaris, Manuel Aivado, Robert H. Singer, Robert A. Coleman & 2 others Amit K. Verma, Ulrich G. Steidl

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

The tumor suppressor p53 is often inactivated via its interaction with endogenous inhibitors mouse double minute 4 homolog (MDM4 or MDMX) or mouse double minute 2 homolog (MDM2), which are frequently overexpressed in patients with acute myeloid leukemia (AML) and other cancers. Pharmacological disruption of both of these interactions has long been sought after as an attractive strategy to fully restore p53-dependent tumor suppressor activity in cancers with wild-type p53. Selective targeting of this pathway has thus far been limited to MDM2-only small-molecule inhibitors, which lack affinity for MDMX. We demonstrate that dual MDMX/MDM2 inhibition with a stapled α-helical peptide (ALRN-6924), which has recently entered phase I clinical testing, produces marked antileukemic effects. ALRN-6924 robustly activates p53-dependent transcription at the single-cell and single-molecule levels and exhibits biochemical and molecular biological on-target activity in leukemia cells in vitro and in vivo. Dual MDMX/MDM2 inhibition by ALRN-6924 inhibits cellular proliferation by inducing cell cycle arrest and apoptosis in cell lines and primary AML patient cells, including leukemic stem cell-Venriched populations, and disrupts functional clonogenic and serial replating capacity. Furthermore, ALRN-6924 markedly improves survival in AML xenograft models. Our study provides mechanistic insight to support further testing of ALRN-6924 as a therapeutic approach in AML and other cancers with wild-type p53.

Original languageEnglish (US)
Article numberaao3003
JournalScience Translational Medicine
Volume10
Issue number436
DOIs
StatePublished - Apr 11 2018

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Leukemia
Acute Myeloid Leukemia
Neoplasms
Therapeutics
Cell Cycle Checkpoints
Heterografts
Stem Cells
Cell Proliferation
Pharmacology
Apoptosis
Cell Line
Peptides
Survival
Population

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Carvajal, L. A., Ben Neriah, D., Senecal, A., Benard, L., Thiruthuvanathan, V., Yatsenko, T., ... Steidl, U. G. (2018). Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia. Science Translational Medicine, 10(436), [aao3003]. https://doi.org/10.1126/scitranslmed.aao3003

Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia. / Carvajal, Luis A.; Ben Neriah, Daniela; Senecal, Adrien; Benard, Lumie; Thiruthuvanathan, Victor; Yatsenko, Tatyana; Narayanagari, Swathi-Rao; Wheat, Justin C.; Todorova, Tihomira I.; Mitchell, Kelly; Kenworthy, Charles; Guerlavais, Vincent; Annis, D. Allen; Bartholdy, Boris A.; Will, Britta; Anampa Mesias, Jesus D.; Mantzaris, Ioannis; Aivado, Manuel; Singer, Robert H.; Coleman, Robert A.; Verma, Amit K.; Steidl, Ulrich G.

In: Science Translational Medicine, Vol. 10, No. 436, aao3003, 11.04.2018.

Research output: Contribution to journalArticle

Carvajal, LA, Ben Neriah, D, Senecal, A, Benard, L, Thiruthuvanathan, V, Yatsenko, T, Narayanagari, S-R, Wheat, JC, Todorova, TI, Mitchell, K, Kenworthy, C, Guerlavais, V, Annis, DA, Bartholdy, BA, Will, B, Anampa Mesias, JD, Mantzaris, I, Aivado, M, Singer, RH, Coleman, RA, Verma, AK & Steidl, UG 2018, 'Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia', Science Translational Medicine, vol. 10, no. 436, aao3003. https://doi.org/10.1126/scitranslmed.aao3003
Carvajal LA, Ben Neriah D, Senecal A, Benard L, Thiruthuvanathan V, Yatsenko T et al. Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia. Science Translational Medicine. 2018 Apr 11;10(436). aao3003. https://doi.org/10.1126/scitranslmed.aao3003
Carvajal, Luis A. ; Ben Neriah, Daniela ; Senecal, Adrien ; Benard, Lumie ; Thiruthuvanathan, Victor ; Yatsenko, Tatyana ; Narayanagari, Swathi-Rao ; Wheat, Justin C. ; Todorova, Tihomira I. ; Mitchell, Kelly ; Kenworthy, Charles ; Guerlavais, Vincent ; Annis, D. Allen ; Bartholdy, Boris A. ; Will, Britta ; Anampa Mesias, Jesus D. ; Mantzaris, Ioannis ; Aivado, Manuel ; Singer, Robert H. ; Coleman, Robert A. ; Verma, Amit K. ; Steidl, Ulrich G. / Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia. In: Science Translational Medicine. 2018 ; Vol. 10, No. 436.
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AU - Carvajal, Luis A.

AU - Ben Neriah, Daniela

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AU - Thiruthuvanathan, Victor

AU - Yatsenko, Tatyana

AU - Narayanagari, Swathi-Rao

AU - Wheat, Justin C.

AU - Todorova, Tihomira I.

AU - Mitchell, Kelly

AU - Kenworthy, Charles

AU - Guerlavais, Vincent

AU - Annis, D. Allen

AU - Bartholdy, Boris A.

AU - Will, Britta

AU - Anampa Mesias, Jesus D.

AU - Mantzaris, Ioannis

AU - Aivado, Manuel

AU - Singer, Robert H.

AU - Coleman, Robert A.

AU - Verma, Amit K.

AU - Steidl, Ulrich G.

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