Early and Late Effects of Pharmacological ALK Inhibition on the Neuroblastoma Transcriptome

Overview

Journal Oncotarget

Specialty Oncology

Date 2018 Jan 2

PMID 29290991

Citations 2

Authors

Shana Claeys

Geertrui Denecker

Robrecht Cannoodt

Candy Kumps

Kaat Durinck

Frank Speleman

Katleen De Preter

Affiliations

Soon will be listed here.

Abstract

Background: Neuroblastoma is an aggressive childhood malignancy of the sympathetic nervous system. Despite multi-modal therapy, survival of high-risk patients remains disappointingly low, underscoring the need for novel treatment strategies. The discovery of activating mutations opened the way to precision treatment in a subset of these patients. Previously, we investigated the transcriptional effects of pharmacological ALK inhibition on neuroblastoma cell lines, six hours after TAE684 administration, resulting in the 77-gene ALK signature, which was shown to gradually decrease from 120 minutes after TAE684 treatment, to gain deeper insight into the molecular effects of oncogenic ALK signaling.

Aim: Here, we further dissected the transcriptional dynamic profiles of neuroblastoma cells upon TAE684 treatment in a detailed timeframe of ten minutes up to six hours after inhibition, in order to identify additional early targets for combination treatment.

Results: We observed an unexpected initial upregulation of positively regulated MYCN target genes following subsequent downregulation of overall MYCN activity. In addition, we identified adrenomedullin (ADM), previously shown to be implicated in sunitinib resistance, as the earliest response gene upon ALK inhibition.

Conclusions: We describe the early and late effects of ALK inhibitor TAE684 treatment on the neuroblastoma transcriptome. The observed unexpected upregulation of ADM warrants further investigation in relation to putative ALK resistance in neuroblastoma patients currently undergoing ALK inhibitor treatment.

Citing Articles

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Entrectinib and other ALK/TRK inhibitors for the treatment of neuroblastoma.

Pacenta H, Macy M Drug Des Devel Ther. 2018; 12:3549-3561.

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