Izquierdo, Elisa;
Carvalho, Diana M;
Mackay, Alan;
Temelso, Sara;
Boult, Jessica KR;
Pericoli, Giulia;
Fernandez, Elisabet;
... Jones, Chris; + view all
(2022)
DIPG Harbors Alterations Targetable by MEK Inhibitors, with Acquired Resistance Mechanisms Overcome by Combinatorial Inhibition.
Cancer Discovery
, 12
(3)
pp. 712-729.
10.1158/2159-8290.CD-20-0930.
Preview |
Text
712.pdf - Published Version Download (7MB) | Preview |
Abstract
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 over-lapping 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.
| Type: | Article |
|---|---|
| Title: | DIPG Harbors Alterations Targetable by MEK Inhibitors, with Acquired Resistance Mechanisms Overcome by Combinatorial Inhibition |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1158/2159-8290.CD-20-0930 |
| Publisher version: | https://doi.org/10.1158/2159-8290.CD-20-0930 |
| Language: | English |
| Additional information: | ©2021 The Authors; Published by the American Association for Cancer Research. This work is licensed under a Creative Commons Attribution 4.0 International License. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10153423 |
Archive Staff Only
 |
View Item |
