The p53 activator overcomes resistance to ALK inhibitors by regulating p53-target selectivity in ALK-driven neuroblastomas

Cell Death Discovery
Makoto MiyazakiMasato Enari

Abstract

Anaplastic lymphoma kinase (ALK) is an oncogenic receptor tyrosine kinase that is activated by gene amplification and mutation in neuroblastomas. ALK inhibitors can delay the progression of ALK-driven cancers, but are of limited use owing to ALK inhibitor resistance. Here, we show that resistance to ALK inhibitor in ALK-driven neuroblastomas can be attenuated by combination treatment with a p53 activator. Either ALK inhibition or p53 activator treatment induced cell cycle arrest, whereas combination treatment induced apoptosis, and prevented tumour relapse both in vitro and in vivo. This shift toward apoptosis, and away from cell-cycle arrest, in the presence of an ALK inhibitor and a p53 activator, is mediated by inhibition of the ALK-AKT-FOXO3a axis leading to a specific upregulation of SOX4. SOX4 cooperates with p53 to upregulate the pro-apoptotic protein PUMA. These data therefore suggest a novel combination therapy strategy for treating ALK-driven neuroblastomas.

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Citations

Sep 5, 2019·Brain Sciences·Salvo Danilo LombardoAlessia Bramanti
Dec 28, 2019·Current Drug Metabolism·Suresh MallepalliRamakrishna Vadde
Jun 9, 2018·Cell Death & Disease·Alessandra Gambacurta, Giuseppe Raschellà
Mar 1, 2019·Cancers·Arthur AubryMichèle Allouche
Dec 15, 2019·International Journal of Molecular Sciences·Consuelo PitolliIvano Amelio
Dec 7, 2019·Journal of Experimental & Clinical Cancer Research : CR·Lucia CappabiancaAndrew Reay Mackay

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Datasets Mentioned

BETA
GSE107354

Methods Mentioned

BETA
flow
flow cytometry
chip
reverse-transcription PCR
xenograft
ELISA
acetylation
nuclear translocation
Feature Extraction
X-ray

Clinical Trials Mentioned

NCT01606878

Software Mentioned

R
Agilent Feature Extraction
Metascape
CompuSyn

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