Article Dans Une Revue Cancer Discovery Année : 2022

DIPG Harbors Alterations Targetable by MEK Inhibitors, with Acquired Resistance Mechanisms Overcome by Combinatorial Inhibition

Elisa Izquierdo
Jessica K.R. Boult
Elisabet Fernandez
  • Fonction : Auteur
Molina Das
Yura Grabovska
  • Fonction : Auteur
Rebecca F. Rogers
Mark Stubbs
  • Fonction : Auteur
Sarita Depani
  • Fonction : Auteur
Patricia O'Hare
  • Fonction : Auteur
Lu Yu
Georgia Roumelioti
  • Fonction : Auteur
Amy Fairchild
  • Fonction : Auteur
Lisa Howell
  • Fonction : Auteur
Susan Picton
  • Fonction : Auteur
Jenny Adamski
  • Fonction : Auteur
Juliet Gray
Bassel Zebian
  • Fonction : Auteur
Lynley Marshall
Maria Vinci
Simon Robinson
Michael Hubank
Darren Hargrave
Chris Jones
  • Fonction : Auteur

Résumé

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 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

Dates et versions

hal-04493160 , version 1 (06-03-2024)

Identifiants

Citer

Elisa Izquierdo, Diana Carvalho, Alan Mackay, Sara Temelso, Jessica K.R. Boult, et al.. DIPG Harbors Alterations Targetable by MEK Inhibitors, with Acquired Resistance Mechanisms Overcome by Combinatorial Inhibition. Cancer Discovery, 2022, 12 (3), pp.712-729. ⟨10.1158/2159-8290.CD-20-0930⟩. ⟨hal-04493160⟩
36 Consultations
0 Téléchargements

Altmetric

Partager

  • More