DIPG Harbors Alterations Targetable by MEK Inhibitors, with Acquired Resistance Mechanisms Overcome by Combinatorial Inhibition.
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Authors
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
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
Document Type
Journal Article
Date
2022-03-01
Date Accepted
2021-10-19
Abstract
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.
Citation
Cancer Discovery, 2022, 12 (3), pp. 712 - 729
Source Title
Cancer Discovery
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
2159-8274
eISSN
2159-8290
2159-8290
2159-8290
Collections
Research Team
Glioma Team
Pre-Clinical MRI
Prote & Metabolomics Fac
Pre-Clinical MRI
Prote & Metabolomics Fac