ArticleResearch square2026
Combinatorial Targeting of Avapritinib-Driven MAP Kinase Activation in High-Grade Glioma.
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Authors and funding
53 authors.
Kallen SchwarkDepartment of Pediatrics, University of Michigan; Ann Arbor, MI, USA.ORCID 0000-0002-0569-9928
Kelsey WinkDepartment of Pediatrics, University of Michigan; Ann Arbor, MI, USA.
Antonella De ColaLudwig Institute for Cancer Research; Oxford, United Kingdom.
Madeline MicleaDepartment of Pediatrics, University of Michigan; Ann Arbor, MI, USA.
Tirth PatelDepartment of Pediatrics, University of Michigan; Ann Arbor, MI, USA.
Seongbae KongDepartment of Pediatrics, University of Michigan; Ann Arbor, MI, USA.
Alina StanczakDepartment of Pediatrics, University of Michigan; Ann Arbor, MI, USA.
Robert DohertyDepartment of Pediatrics, University of Michigan; Ann Arbor, MI, USA.
Ashley PearsonDepartment of Pediatrics, University of Michigan; Ann Arbor, MI, USA.
Bhuvna MurthyDepartment of Pediatrics, University of Michigan; Ann Arbor, MI, USA.
Benison LauDepartment of Pediatrics, University of Michigan; Ann Arbor, MI, USA.
Rodrigo T CartaxoDepartment of Pediatrics, University of Michigan; Ann Arbor, MI, USA.
Dana MessingerDepartment of Pediatrics, University of Michigan; Ann Arbor, MI, USA.
Sunjong JiDepartment of Pediatrics, University of Michigan; Ann Arbor, MI, USA.ORCID 0000-0002-6516-2380
Jack WaddenDepartment of Pediatrics, University of Michigan; Ann Arbor, MI, USA.
Madison ClausenDepartment of Pediatrics, University of Michigan; Ann Arbor, MI, USA.
Daniel de la NavaDepartment of Pediatrics, University of Michigan; Ann Arbor, MI, USA.
Peyton GoetheDepartment of Neurosurgery, University of Michigan; Ann Arbor, MI, 48109, USA.
Fareen MomenDepartment of Pediatrics, University of Michigan; Ann Arbor, MI, USA.
Tiffany AdamDepartment of Pediatrics, University of Michigan; Ann Arbor, MI, USA.
Aria HutchinsonDepartment of Pediatrics, University of Michigan; Ann Arbor, MI, USA.
Michael NiculceaDepartment of Pediatrics, University of Michigan; Ann Arbor, MI, USA.
Habib SerhanDepartment of Internal Medicine, University of Michigan; Ann Arbor, MI, USA.
Nathan M MerrillDepartment of Internal Medicine, University of Michigan; Ann Arbor, MI, USA.ORCID 0000-0003-0757-3680
Amy EdmondsDepartment of Pediatrics, University of Michigan; Ann Arbor, MI, USA.
Lisa MayrDepartment of Pediatrics and Adolescent Medicine, Medical University of Vienna; Vienna, Austria.ORCID 0000-0002-6841-0749
Sina NeyaziDepartment of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School; Boston, MA, USA.ORCID 0000-0002-9861-2325
Denise P MuñozDepartment of Radiation Oncology, University of California San Francisco; San Francisco, CA, USA.
Yeonjoo HwangDepartment of Radiation Oncology, University of California San Francisco; San Francisco, CA, USA.
Nicholas K NuechterleinDepartment of Pathology, University of Michigan; Ann Arbor, MI, USA.ORCID 0000-0002-9599-0865
Ester Calvo FernándezDepartment of Systems Biology, Columbia University; New York, NY, USA.
Andrea CalifanoDepartment of Systems Biology, Columbia University; New York, NY, USA.ORCID 0000-0003-4742-3679
Jovana PavisicDepartment of Pediatrics, Columbia University; New York, NY, USA.
Hugh GartonDepartment of Neurosurgery, University of Michigan; Ann Arbor, MI, 48109, USA.
Rama RaoDepartment of Pediatrics, University of Michigan; Ann Arbor, MI, USA.
Santhosh A UpadhyayaDepartment of Pediatrics, University of Michigan; Ann Arbor, MI, USA.
Mary SkrypekDepartment of Pediatric Hematology-Oncology, Children's Minnesota; Minneapolis, MN, USA.
Anne E BendelDepartment of Pediatric Hematology-Oncology, Children's Minnesota; Minneapolis, MN, USA.ORCID 0000-0002-2062-0974
Mina LobbousDepartment of Neurology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University; Cleveland, OH, USA.
Darren KlawinskiDepartment of Pediatrics, Nemours Children's Health System; Jacksonville, FL, USA.
Sofia D MerajverDepartment of Internal Medicine, University of Michigan; Ann Arbor, MI, USA.
Mateusz P KoptyraDepartment of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia; Philadelphia, PA, USA.
Adam C ResnickDepartment of Surgery, Children's Hospital of Philadelphia; Philadelphia, PA, USA.
Javad NazarianDepartment of Pediatrics, University Children's Hospital, University of Zurich, Zurich, Switzerland.ORCID 0000-0002-1951-9828
Sriram VennetiDepartment of Pathology, University of Michigan; Ann Arbor, MI, USA.
Sebastian M WaszakSchool of Life Sciences, École Polytechnique Fédérale de Lausanne; Lausanne, Switzerland.
Lukas ChavezDepartment of Medicine, University of California San Diego; La Jolla, CA, USA.
Johannes GojoDepartment of Pediatrics and Adolescent Medicine, Medical University of Vienna; Vienna, Austria.ORCID 0000-0002-8113-3416
Mariella G FilbinDepartment of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School; Boston, MA, USA.ORCID 0000-0002-2613-8126
Alexander BeckCenter for Neuropathology, Ludwig Maximillian University of Munich; Munich, Germany.ORCID 0000-0001-8641-7832
Manav PathaniaLudwig Institute for Cancer Research; Oxford, United Kingdom.
Jean-Philippe F CoppeDepartment of Radiation Oncology, University of California San Francisco; San Francisco, CA, USA.ORCID 0000-0002-0890-8326
Carl KoschmannDepartment of Pediatrics, University of Michigan; Ann Arbor, MI, USA.
Funding
MICHIGAN MEDICAL SCIENTIST TRAINING PROGRAMT32GM007863 · NIGMS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI COLLINS, KATHLEEN L. · 1985 to 2024
$38.3MTraining Program in Tumor MicroenvironmentT32CA009676 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Maria G Castro, Analisa Virginia DiFeo · 1992 to 2026
$7.3MTargeting EGFR/FOXG1-mediated resistance to ONC201 in H3K27M-mutant diffuse midline gliomaR01NS124607 · NINDS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Carl J Koschmann · 2022 to 2026
$2.2MThe role of ATRX mutation in the epigenetic dysregulation of cell cycle in pediatric high-grade gliomaR01NS119231 · NINDS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI KOSCHMANN, CARL J · 2021 to 2025
$1.9MAnalytical and Clinical Validation of an H3K27M ctDNA Assay for Diffuse Midline Glioma (DMG) SurveillanceUH2CA302680 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Carl J Koschmann · 2025 to 2026
$421kNCI NIH HHS T32 CA009676NCI NIH HHS UH2 CA302680NIGMS NIH HHS T32 GM007863NINDS NIH HHS R01 NS119231NINDS NIH HHS R01 NS124607
Abstract
PDGFRA alterations define a high-risk subset of high-grade glioma (HGG), yet targeted therapies have yielded limited and transient benefit. Here, we show that the CNS-penetrant PDGFRA inhibitor avapritinib induces sustained MAPK pathway activation at supratherapeutic dosing, revealing a therapy-induced adaptive vulnerability. High-dimensional kinome profiling (>900 nodes) and
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.