MK2 inhibition induces p53-dependent senescence in glioblastoma cells

Athena F. Phoa, Ariadna Recasens, Fadi M.S. Gurgis, Tara A. Betts, Sharleen V. Menezes, Diep Chau, Kristiina Nordfors, Joonas Haapasalo, Hannu Haapasalo, Terrance G. Johns, Brett W. Stringer, Bryan W. Day, Michael E. Buckland, Najoua Lalaoui, Lenka Munoz

Research output: Contribution to journalArticle

Abstract

MAPK-activated protein kinase 2 (MK2) has diverse roles in cancer. In response to chemotherapy, MK2 inhibition is synthetically lethal to p53-deficiency. While TP53 deletion is rare in glioblastomas, these tumors often carry TP53 mutations. Here, we show that MK2 inhibition strongly attenuated glioblastoma cell proliferation through p53wt stabilization and senescence. The senescence-inducing efficacy of MK2 inhibition was particularly strong when cells were co-treated with the standard-of-care temozolomide. However, MK2 inhibition also increased the stability of p53 mutants and enhanced the proliferation of p53-mutant stem cells. These observations reveal that in response to DNA damaging chemotherapy, targeting MK2 in p53-mutated cells produces a phenotype that is distinct from the p53-deficient phenotype. Thus, MK2 represents a novel drug target in 70% glioblastomas harboring intact TP53 gene. However, targeting MK2 in tumors with TP53 mutations may accelerate disease progression. These findings are highly relevant since TP53 mutations occur in over 50% of all cancers.

Original languageEnglish
Article number654
Number of pages19
JournalCancers
Volume12
Issue number3
DOIs
Publication statusPublished - 11 Mar 2020
Externally publishedYes

Bibliographical note

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution(CC BY) license (http://creativecommons.org/licenses/by/4.0/)

Keywords

  • Glioblastoma
  • MK2
  • P53
  • Senescence
  • Temozolomide

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  • Cite this

    Phoa, A. F., Recasens, A., Gurgis, F. M. S., Betts, T. A., Menezes, S. V., Chau, D., Nordfors, K., Haapasalo, J., Haapasalo, H., Johns, T. G., Stringer, B. W., Day, B. W., Buckland, M. E., Lalaoui, N., & Munoz, L. (2020). MK2 inhibition induces p53-dependent senescence in glioblastoma cells. Cancers, 12(3), [654]. https://doi.org/10.3390/cancers12030654