Therapeutic-Induced Cellular Plasticity in IDH-Mutant Gliomas: From De-Differentiation to Lineage Reinforcement

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Avishay, Spitzer, Tel Aviv Sourasky Medical Center, Simon, Gritsch, Massachusetts General Hospital, Masashi, Nomura, Massachusetts General Hospital, Kevin, Johnson, Yale School of Medicine, Frederick, Varn, Yale School of Medicine, Luciano, Garofano, University of Miami, Keith, Ligon, Dana-Farber Cancer Institute,

Daniel, Cahill, Massachusetts General Hospital, Anna, Lasorella, University of Miami, Antonio, Iavarone, University of Miami

Roel, Verhaak, Yale School of Medicine, Mario, Suva, Massachusetts General Hospital,

Itay, Tirosh, Weizmann Institute of Science

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Objective:

IDH-mutant gliomas are aggressive and lethal brain tumors, yet the mechanisms by which therapies influence cellular evolution and contribute to treatment resistance remain unclear. Here, we investigate how standard of care (chemo-radiation) and mutant IDH inhibitors (IDHi) shape the cellular dynamics of IDH-mutant gliomas, aiming to understand their therapeutic impact and mechanisms of resistance.

 

Methods:

We analyzed two independent cohorts of IDH-mutant gliomas: one consisting of longitudinal samples (treatment-naïve and exposed) from patients treated with chemo-radiation and another from patients treated with IDHi (Ivosidenib or Vorasidenib). Using single-nucleus RNA sequencing, chromatin accessibility profiling, and bulk DNA sequencing, we profiled 75 tumors from 35 patients in the standard of care cohort. Additionally, we performed single-cell analysis on IDH-mutant oligodendrogliomas sampled on-treatment from patients treated with IDHi.

 

Results:

In the chemo-radiation cohort, disease progression was associated with de-differentiation of malignant cells, with a shift toward proliferative and mesenchymal-like phenotypes, particularly in tumors acquiring DNA hypermutation or CDKN2A loss. Increased mesenchymal-like cell states correlated with enhanced macrophage infiltration and poorer survival. In contrast, IDH inhibition was associated with a robust differentiation of malignant cells toward the astrocytic lineage, accompanied by a depletion of stem-like and proliferative populations. Mutations in NOTCH1 were associated with diminished differentiation and reduced responsiveness to IDHi.

 

Conclusions:

Our results define a central therapeutic axis in IDH-mutant gliomas: chemo-radiation is associated with cellular de-differentiation and aggressive phenotypes, while IDH inhibition induces differentiation and limits proliferative potential. These findings underscore the potential of differentiation therapy in IDH-mutant gliomas and highlight the need to account for treatment-induced cellular plasticity in developing durable therapeutic strategies.