DIPG Harbors Alterations Targetable by MEK Inhibitors, with Acquired Resistance Mechanisms Overcome by Combinatorial Inhibition.
Date
2022-03-01ICR Author
Author
Izquierdo, E
Carvalho, DM
Mackay, A
Temelso, S
Boult, JKR
Pericoli, G
Fernandez, E
Das, M
Molinari, V
Grabovska, Y
Rogers, RF
Ajmone-Cat, MA
Proszek, PZ
Stubbs, M
Depani, S
O'Hare, P
Yu, L
Roumelioti, G
Choudhary, JS
Clarke, M
Fairchild, AR
Jacques, TS
Grundy, RG
Howell, L
Picton, S
Adamski, J
Wilson, S
Gray, JC
Zebian, B
Marshall, LV
Carceller, F
Grill, J
Vinci, M
Robinson, SP
Hubank, M
Hargrave, D
Jones, C
Type
Journal Article
Metadata
Show full item recordAbstract
UNLABELLED: The survival of children with diffuse intrinsic pontine glioma (DIPG) remains dismal, with new treatments desperately needed. In a prospective biopsy-stratified clinical trial, we combined detailed molecular profiling and drug screening in newly established patient-derived models in vitro and in vivo. We identified in vitro sensitivity to MEK inhibitors in DIPGs harboring MAPK pathway alterations, but treatment of patient-derived xenograft models and a patient at relapse failed to elicit a significant response. We generated trametinib-resistant clones in a BRAFG469V model through continuous drug exposure and identified acquired mutations in MEK1/2 with sustained pathway upregulation. These cells showed hallmarks of mesenchymal transition and expression signatures overlapping with inherently trametinib-insensitive patient-derived cells, predicting sensitivity to dasatinib. Combined trametinib and dasatinib showed highly synergistic effects in vitro and on ex vivo brain slices. We highlight the MAPK pathway as a therapeutic target in DIPG and show the importance of parallel resistance modeling and combinatorial treatments for meaningful clinical translation. SIGNIFICANCE: We report alterations in the MAPK pathway in DIPGs to confer initial sensitivity to targeted MEK inhibition. We further identify for the first time the mechanism of resistance to single-agent targeted therapy in these tumors and suggest a novel combinatorial treatment strategy to overcome it in the clinic. This article is highlighted in the In This Issue feature, p. 587.
Collections
Subject
Child
Humans
Brain Stem Neoplasms
Cell Line, Tumor
Dasatinib
Mitogen-Activated Protein Kinase Kinases
Neoplasm Recurrence, Local
Prospective Studies
Protein Kinase Inhibitors
Research team
Glioma Team
Pre-Clinical MRI
Prote & Metabolomics Fac
Language
eng
Date accepted
2021-10-19
License start date
2022-03-01
Citation
Cancer Discovery, 2022, 12 (3), pp. 712 - 729
Publisher
AMER ASSOC CANCER RESEARCH