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

2021; American Association for Cancer Research; Volume: 12; Issue: 3 Linguagem: Inglês

10.1158/2159-8290.cd-20-0930

2159-8290

Elisa Izquierdo, Diana Carvalho, Alan Mackay, Sara Temelso, Jessica K.R. Boult, Giulia Pericoli, Elisabet Fernandez, Molina Das, Valeria Molinari, Yura Grabovska, Rebecca Rogers, Maria Antonietta Ajmone‐Cat, Paula Proszek, Mark Stubbs, Sarita Depani, Patricia O’Hare, Lu Yu, Georgia Roumelioti, Jyoti S. Choudhary, Matthew Clarke, Amy R. Fairchild, Thomas S. Jacques, Richard G. Grundy, Lisa Howell, Susan Picton, Jenny Adamski, Shaun Wilson, Juliet C. Gray, Bassel Zebian, Lynley V. Marshall, Fernando Carceller, Jacques Grill, Maria Vinci, Simon P. Robinson, Michael Hubank, Darren Hargrave, Chris Jones,

Cellular Mechanics and Interactions

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.