DIPG harbour alterations targetable by MEK inhibitors, with acquired resistance mechanisms overcome by combinatorial inhibition

Abstract

The survival of children with 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 harbouring MAPK pathway alterations, however treatment of PDX models and a patient at relapse failed to elicit a significant response. We generated trametinib-resistant clones in a BRAF_G469V model through continuous drug exposure, and identified acquired mutations in MEK1/2 with sustained pathway up-regulation. 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 modelling and combinatorial treatments for meaningful clinical translation.

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