Multiomics Insights into the Mechanism and Enhanced Efficacy of Tumor Treating Fields (TTFields) Therapy in Glioblastoma

Glioma is an aggressive brain tumor that requires challenging
treatments.
Tumor Treating Fields (TTFields), an FDA-approved therapy for glioblastoma
(GBM), pleural mesothelioma, and platinum-refractory metastatic nonsmall
cell lung cancer (in combination with PD-1/PD-L1 inhibitors or docetaxel),
employs specific frequency electric fields to disrupt cell division
and enhance treatment efficacy. However, their molecular mechanisms
remain unclear. This study aimed to elucidate these mechanisms and
optimize the therapeutic potential of TTFields through quantitative
proteomics, phosphoproteomics, and glycoproteomics. Pathway analysis
of the proteomics revealed that TTFields impact the cell cycle, DNA
repair, autophagy, and DNA replication. Phosphoproteomic studies further
demonstrated a marked decline in the activity of key kinases ABL1
and PDK1, while glycoproteomics highlighted disruptions in cell adhesion
and ECM-receptor interactions. Notably, proteomic analysis identified
an upregulation of PARP1 and BRD4 protein levels, suggesting a previously
unrecognized resistance mechanism. Consistently, combining TTFields
with inhibitors targeting these proteins significantly enhanced the
treatment efficacy in U87 cells. Thus, this study uncovers comprehensive
molecular mechanisms underlying TTFields’ effects on GBM cells
and supports the development of concomitant therapies to enhance treatment
efficacy.