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PI3K/AKT/mTOR signaling pathway activity in IDH-mutant diffuse glioma and clinical implications
Esraa Mohamed1, Anupam Kumar1, Yalan Zhang1
1Department of Neurological Surgery, Brain Tumor Center, University of California, San Francisco, San Francisco, California, USA.
Background:
IDH-mutant diffuse gliomas are heterogeneous, and improved methods for optimal patient therapeutic stratification are needed. PI3K/AKT/mTOR signaling activity can drive disease progression and potential therapeutic inhibitors of the pathway are available. Yet, the prevalence of PI3K/AKT/mTOR signaling pathway activity in IDH-mutant glioma is unclear and few robust strategies to assess activity in clinical samples exist.
Methods:
PI3K/AKT/mTOR signaling pathway activity was evaluated in a retrospective cohort of 132 IDH-mutant diffuse glioma (91 astrocytoma and 41 oligodendroglioma, 1p/19q-codeleted) through quantitative multiplex immunoprofiling using phospho-specific antibodies for PI3K/AKT/mTOR pathway members, PRAS40, RPS6, and 4EBP1, and tumor-specific anti-IDH1 R132H. Expression levels were correlated with genomic evaluation of pathway intrinsic genes and univariate and multivariate Cox proportional hazard regression models were used to evaluate the relationship with outcome.
Results:
Tumor-specific expression of p-PRAS40, p-RPS6, and p-4EBP1 was common in IDH-mutant diffuse glioma and increased with CNS WHO grade from 2 to 3. Genomic analysis predicted pathway activity in 21.7% (13/60) while protein evaluation identified active PI3K/AKT/mTOR signaling in 56.6% (34/60). Comparison of expression in male versus female patients suggested sexual dimorphism. Of particular interest, when adjusting for clinical prognostic factors, the level of phosphorylation of RPS6 was strongly associated with PFS (P < .005). Phosphorylation levels of both PRAS40 and RPS6 showed an association with PFS in univariate analysis.
Conclusions:
Our study emphasizes the value of proteomic assessment of signaling pathway activity in tumors as a means to identify relevant oncogenic pathways and potentially as a biomarker for identifying aggressive disease.
Insights
Assessing PI3K/AKT/mTOR pathway activity in IDH-mutant gliomas using proteomic methods reveals common pathway activation. This protein-based approach may identify aggressive disease and aid therapeutic stratification.
Area of Science:
- Neuro-oncology
- Molecular pathology
- Cancer signaling pathways
Background:
- IDH-mutant diffuse gliomas are heterogeneous, necessitating improved therapeutic stratification.
- PI3K/AKT/mTOR signaling is implicated in glioma progression, but its prevalence in IDH-mutant gliomas is unclear.
- Robust methods for assessing PI3K/AKT/mTOR pathway activity in clinical glioma samples are limited.
Purpose of the Study:
- To evaluate PI3K/AKT/mTOR signaling pathway activity in IDH-mutant diffuse gliomas.
- To correlate pathway activity with genomic data and patient outcomes.
- To explore proteomic assessment as a biomarker for aggressive disease.
Main Methods:
- Quantitative multiplex immunoprofiling of 132 IDH-mutant gliomas using phospho-specific antibodies.
- Assessment of PI3K/AKT/mTOR pathway members (PRAS40, RPS6, 4EBP1) and IDH1 R132H.
- Correlation with genomic data and survival analysis using Cox regression models.
Main Results:
- Active PI3K/AKT/mTOR signaling was detected in 56.6% of gliomas via protein evaluation, compared to 21.7% by genomic analysis.
- Pathway activation increased with higher CNS WHO grade.
- Phosphorylation of RPS6 strongly correlated with progression-free survival (PFS), suggesting its potential as a prognostic biomarker.
Conclusions:
- Proteomic assessment of signaling pathway activity is valuable for identifying oncogenic pathways in tumors.
- This approach can serve as a biomarker for identifying aggressive IDH-mutant glioma.
- The findings support the utility of protein-based pathway analysis for clinical decision-making.
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