Study

Targets of MEK inhibition in DIPG

Study ID Alternative Stable ID Type
EGAS00001004495 Other

Study Description

The survival of children with diffuse intrinsic pontine glioma (DIPG) remains dismal, with new treatments desperately needed. In the era of precision medicine, targeted therapies represent an exciting treatment opportunity, yet resistance can rapidly emerge, playing an important role in treatment failure. In a prospective biopsy-stratified clinical trial, we combined detailed molecular profiling (methylation BeadArray, exome, RNAseq, phospho-proteomics) linked to drug screening in newly-established patient-derived models of DIPG in vitro and in vivo. We identified a high degree of in vitro sensitivity to the MEK inhibitor trametinib in samples which harboured genetic alterations targeting the MAPK pathway, including the non-canonical BRAF_G469V mutation, and those affecting PIK3R1 and NF1. However, treatment of PDX models and of a patient with trametinib at relapse failed to elicit a significant response. We generated trametinib-resistant clones in the BRAF_G469V model through continuous drug exposure, and identified acquired mutations in MEK1/2 (MEK1_K57N, MEK1_I141S and ... (Show More)

Study Datasets 2 datasets.

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Dataset ID Description Technology Samples
EGAD00001008211
Whole exome sequencing of Diffuse intrinsic pontine gliomas, primary patient derived DIPG cell cultures and isogenic trametinib resistant clones
Illumina NovaSeq 6000 56
EGAD00001008212
RNA sequencing of Diffuse intrinsic pontine gliomas, primary patient derived DIPG cell cultures and isogenic trametinib resistant clones
NextSeq 500 28

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