ArticleCancer discovery2022
DIPG Harbors Alterations Targetable by MEK Inhibitors, with Acquired Resistance Mechanisms Overcome by Combinatorial Inhibition.
Article in Cancer discovery, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 34 citations in OpenAlex.
- RAS/MAPK inhibition in pediatric gliomas.Neuro-oncology advances · 2026Review
- Transcriptomics-guided high-throughput drug screening identifies potent therapies for P53 pathway altered DIPG/DMG.Neuro-oncology · 2026Article
- The Spectrum of IDH- and H3-Wildtype High-Grade Glioma Subgroups Occurring across Teenage and Young Adult Patient Populations.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Article
- Opportunities and challenges for patient-derived models of brain tumors in functional precision medicine.NPJ precision oncology · 2025Review
- MYH9 promotes malignant progression of glioma cells through regulating β-catenin stability via epithelial-mesenchymal transition signaling pathway.Scientific reports · 2025Article
- Effects of combination therapy of a CDK4/6 and MEK inhibitor in diffuse midline glioma preclinical models.PloS one · 2025Article
- The positive feedback loop between SP1 and MAP2K2 significantly drives resistance to VEGFR inhibitors in clear cell renal cell carcinoma.International journal of biological sciences · 2025Article
- Expert consensus on the diagnosis and treatment of solid tumors with BRAF mutations.Innovation (Cambridge (Mass.)) · 2024Review
- Gliomatosis cerebri in children: A poor prognostic phenotype of diffuse gliomas with a distinct molecular profile.Neuro-oncology · 2024Article
- Review
- Diffuse midline glioma invasion and metastasis rely on cell-autonomous signaling.Neuro-oncology · 2024Article
- Case Report: Low-grade glioma withFrontiers in surgery · 2024Article
- A multidimensional platform of patient-derived tumors identifies drug susceptibilities for clinical lenvatinib resistance.Acta pharmaceutica Sinica. B · 2024Article
- Molecular diagnostic tools for the World Health Organization (WHO) 2021 classification of gliomas, glioneuronal and neuronal tumors; an EANO guideline.Neuro-oncology · 2023Article
- High-Throughput Drug Screening of Primary Tumor Cells Identifies Therapeutic Strategies for Treating Children with High-Risk Cancer.Cancer research · 2023Article
- A Compendium of Syngeneic, Transplantable Pediatric High-Grade Glioma Models Reveals Subtype-Specific Therapeutic Vulnerabilities.Cancer discovery · 2023Article
- Therapeutic avenues for targeting treatment challenges of diffuse midline gliomas.Neoplasia (New York, N.Y.) · 2023Review
- Article
- Applying single cell multi-omic analyses to understand treatment resistance in pediatric high grade glioma.Frontiers in pharmacology · 2023Review
- Inter and intra-tumor heterogeneity of paediatric type diffuse high-grade gliomas revealed by single-cell mass cytometry.Frontiers in oncology · 2022Article
Corrections and comments
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Authors and funding
37 authors at 14 institutions in 5 countries.
Funding
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.
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Registered trials
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.