EXTH-15. Combinatorial targeting of avapritinib-driven MAPK activation in pediatric high-grade glioma

Abstract PDGFRA is a frequently altered gene in pHGG, driving aggressive behavior and worse prognoses. Avapritinib, a CNS-penetrant inhibitor of mutated PDGFRα and KIT kinases, has shown promise in vitro, in vivo, and in pHGG patients. Single-agent trials in pHGG often fail due to disease heterogeneity and resistance development; for greater chances of success, rational combinatorial therapy will be needed. We performed a high-throughput kinase-activity mapping (HT-KAM) screen to detect the catalytic activity of >900 kinase-substrate nodes in our pHGG models. Supraphysiological doses of 1uM avapritinib treatment of PDGFRA-altered pHGG cells in vitro resulted in sustained activation of the MAPK pathway. Dose-dependent pERK upregulation in response to avapritinib was confirmed in multiple pHGG in vitro and in vivo models from 100 nM-10 µM. Single-cell RNAseq analysis of avapritinib-treated pHGG tumors in vivo demonstrated that cycling OPC-like cells were primarily responsible for increased expression of MAPK pathway genes. Furthermore, upregulation of the ERK-driven anti-apoptotic protein MCL-1 was found in avapritinib-treated pHGG cells in vitro, and MCL-1 knockout increased sensitivity to avapritinib. Combinatorial treatment of pHGG models with MEK (selumetinib, trametinib), ERK (ulixertinib) and integrated stress/ERK inhibitors (ONC201, ONC206) in vitro eradicated pERK activity. MEK inhibitors demonstrated the strongest knockdown of MAPK activity via HT-KAM assessment in vitro with combinatorial survival benefit in vivo. A tumor organoid model from a patient with PDGFRα D842V-mutant CNS tumor with progression on avapritinib showed synergistic benefit with trametinib treatment. Based on these data, we treated a cohort of five brain tumor patients with avapritinib and a MEK inhibitor (selumetinib or trametinib). A patient with an un-resected PDGFRα-mutant pHGG treated with avapritinib and selumetinib prior to progression demonstrated complete and ongoing tumor regression (12 months+). Considering sustained MAPK activation identified in our study, dual avapritinib-MAPK targeted treatment may be an effective approach for PDGFRα-driven pHGG.

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Publication Details

Journal
Neuro-Oncology
Published
2025-11-01
DOI
https://doi.org/10.1093/neuonc/noaf201.1349
Primary Topic
Glioma Diagnosis and Treatment
Type
article
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article

EXTH-15. Combinatorial targeting of avapritinib-driven MAPK activation in pediatric high-grade glioma

Anne Bendel, Carl Johannes Koschmann, Mariella G. Filbin, Tiffany Adam et al.
Neuro-Oncology
Glioma Diagnosis and Treatment
article

EXTH-15. Combinatorial targeting of avapritinib-driven MAPK activation in pediatric high-grade glioma

Anne Bendel, Carl Johannes Koschmann, Mariella G. Filbin, Tiffany Adam, Javad Nazarian, Kallen Schwark, Ester Calvo Fernández, Rodrigo T. Cartaxo, Sunjong Ji, Hugh Garton, Madeline Miclea, Dana Messinger, Amy T. Edmonds, T. Rama Rao, Sriram Venneti, Nathan M. Merrill, Robert Doherty, Mary Skrypek, Johannes Gojo, Alexander Beck, Mina Lobbous, Darren Klawinski, Jovana Pavisic, Aleksandra Stańczak, Andrea Califano, Krista C.J. Wink, Sebastian M. Waszak, Lukas Chávez, Michael Niculcea, Habib A. Serhan, Seongbae Kong, Sofia Diana Merajver, Nicholas Nuechterlein, Denise P. Muñoz, Mateusz Koptyra, Sina Neyazi, Santhosh A. Upadhyaya, Benison C. Lau, Lisa Mayr, Jack Wadden, Adam Resnick, Amy K. Hutchinson, Madison Clausen, Jean-Philippe Coppé, Tirth K. Patel, Fareen Momen
article en

Abstract

Abstract PDGFRA is a frequently altered gene in pHGG, driving aggressive behavior and worse prognoses. Avapritinib, a CNS-penetrant inhibitor of mutated PDGFRα and KIT kinases, has shown promise in vitro, in vivo, and in pHGG patients. Single-agent trials in pHGG often fail due to disease heterogeneity and resistance development; for greater chances of success, rational combinatorial therapy will be needed. We performed a high-throughput kinase-activity mapping (HT-KAM) screen to detect the catalytic activity of >900 kinase-substrate nodes in our pHGG models. Supraphysiological doses of 1uM avapritinib treatment of PDGFRA-altered pHGG cells in vitro resulted in sustained activation of the MAPK pathway. Dose-dependent pERK upregulation in response to avapritinib was confirmed in multiple pHGG in vitro and in vivo models from 100 nM-10 µM. Single-cell RNAseq analysis of avapritinib-treated pHGG tumors in vivo demonstrated that cycling OPC-like cells were primarily responsible for increased expression of MAPK pathway genes. Furthermore, upregulation of the ERK-driven anti-apoptotic protein MCL-1 was found in avapritinib-treated pHGG cells in vitro, and MCL-1 knockout increased sensitivity to avapritinib. Combinatorial treatment of pHGG models with MEK (selumetinib, trametinib), ERK (ulixertinib) and integrated stress/ERK inhibitors (ONC201, ONC206) in vitro eradicated pERK activity. MEK inhibitors demonstrated the strongest knockdown of MAPK activity via HT-KAM assessment in vitro with combinatorial survival benefit in vivo. A tumor organoid model from a patient with PDGFRα D842V-mutant CNS tumor with progression on avapritinib showed synergistic benefit with trametinib treatment. Based on these data, we treated a cohort of five brain tumor patients with avapritinib and a MEK inhibitor (selumetinib or trametinib). A patient with an un-resected PDGFRα-mutant pHGG treated with avapritinib and selumetinib prior to progression demonstrated complete and ongoing tumor regression (12 months+). Considering sustained MAPK activation identified in our study, dual avapritinib-MAPK targeted treatment may be an effective approach for PDGFRα-driven pHGG.

Neuro-OncologyVol. 27(Supplement_5)
Cleveland Clinic (US), Memorial Sloan Kettering Cancer Center (US), Children's Hospital of Philadelphia (US), Children's National (US), University of California, San Francisco (US), University of Michigan (US), Minnesota West Community & Technical College (US), University of California San Diego (US), Nemours Children's Health System (US), Dana-Farber Cancer Institute (US), Children's Minnesota (US), Nemours Children's Clinic (US), École Polytechnique Fédérale de Lausanne (CH), Medical University of Vienna (AT), Columbia University (US), Ludwig-Maximilians-Universität München (DE)
Openalex Percentile: Top 52%
Glioma Diagnosis and Treatment
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