Case Report Identifies Resistance Mutations in IDH-Mutant Glioma, Pointing to Targets for Drug Development
Julie Miller, MD, PhD
Daniel Cahill, MD, PhD
IDH-mutant gliomas, a form of brain cancer that is most common in adults younger than age 45, can be treated with vorasidenib, a recently approved targeted therapy. However, many patients have tumors that are resistant to this treatment. Identifying mutations that cause this resistance is a key step in drug development.
In a letter to the editor published in NeuroOncology, researchers from the Mass General Brigham Cancer Institute, the Mass General Brigham Neuroscience Institute and the Mass General Brigham Department of Pathology, alongside key collaborators at Maine Health and the Weizmann Institute, describe the case of a 31-year-old patient whose tumor continued to grow during vorasidenib treatment.
Using genetic testing, the team found that her tumor had acquired two new NOTCH1 mutations, not present in the original tumor. Both occurred in a region where NOTCH1 mutations are known to impair the function of a protein that plays a key role in cell communication. The finding builds on previous laboratory research suggesting that loss of NOTCH1 function could make tumor cells less responsive to IDH inhibition. The researchers also identified an additional IDH mutation in a subpopulation of tumor cells that could potentially contribute to resistance.
Identifying resistant mutations helps clinicians understand why some patients may respond well while others don’t and tailor treatment accordingly. Insights from this patient case could help motivate the development of next-generation treatment strategies designed to overcome or prevent resistance to IDH inhibitors.
Published in NeuroOncology on October 15, 2026 | Read the paper: “Emergence of inactivating NOTCH1 mutations in an IDH-mutant astrocytoma with clinical resistance to vorasidenib treatment”
Summary reviewed by: Daniel Cahill, MD, PhD, co-corresponding author; Julie Miller, MD, PhD, co-corresponding author