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

Cancer Discov. 2022 Mar 1;12(3):712-729. doi: 10.1158/2159-8290.CD-20-0930.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain Stem Neoplasms* / drug therapy
  • Brain Stem Neoplasms* / genetics
  • Brain Stem Neoplasms* / pathology
  • Cell Line, Tumor
  • Child
  • Dasatinib / pharmacology
  • Dasatinib / therapeutic use
  • Glutamates
  • Humans
  • Mitogen-Activated Protein Kinase Kinases
  • Neoplasm Recurrence, Local* / drug therapy
  • Prospective Studies
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use

Substances

  • Glutamates
  • Protein Kinase Inhibitors
  • dipinacoline glutamate
  • Mitogen-Activated Protein Kinase Kinases
  • Dasatinib