# Identification and targeting oxidative phosphorylation/glycolysis to overcome anti-CSF-1R therapy resistance in glioblastoma

## TL;DR

This study identifies a new way to improve glioblastoma treatment by targeting energy pathways that cause resistance to existing therapies.

## Contribution

The study introduces translatome profiling to uncover resistance mechanisms and proposes drug combinations to overcome anti-CSF-1R therapy resistance in GBM.

## Key findings

- Translatome profiling identified oxidative phosphorylation/glycolysis as a resistance mechanism to anti-CSF-1R therapy in GBM.
- Piperlongumine or vorinostat reversed this resistance in vitro and in vivo, improving survival when combined with PLX3397 and TMZ.
- The triple therapy significantly extended survival in a mouse model of GBM.

## Abstract

The standard care of glioblastomas (GBM) confers limited survival benefit for patients due to the rapid tumor recurrence. Targeting tumor-associated macrophages/microglia via colony-stimulating factor 1 receptor (CSF-1R) inhibition is potentially effective in suppressing GBM recurrence. However, clinical trials of CSF-1R inhibitors failed to achieve their goal due to GBM resistance to anti-CSF-1R therapy. Here, we identified and verified key resistance mechanisms of anti-CSF-1R therapy by translatome profiling-combined analyses. To solve above problem, we have established a highly stable and refractory mouse G422TN-GBM model, in which temozolomide (TMZ) is the most effective monotherapy but can only slightly extend animal survival. To identify effective resistance mechanism of anti-CSF1R therapy in GBM, we first apply the Translating ribosome affinity purification (TRAP) RNA-sequencing techniques in GBM tissues, which have previously used in neuroscience. TRAP-seq identified oxidative phosphorylation/glycolysis as anti-CSF1R therapy resistance mechanism, and it’s combined with Cancer Therapeutics Response Portal (CTRP) identified piperlongumine (PL) or vorinostat (SAHA) as targeting drugs. PL or SAHA enhanced PLX3397 efficacy by reversing oxidative phosphorylation/glycolysis dysregulation in vitro and in vivo. The triple combination of PLX3397, TMZ, and PL/SAHA significantly improved survival in G422TN-GBM mice. In conclusion, targeting oxidative phosphorylation/glycolysis by PL or SAHA prominently improves therapeutic efficacy of PLX3397 + TMZ in GBM, which deserves priority for clinical trials. Our study also reveals that translatome profiling is efficient for uncovering drug-resistant targets.