Journal of experimental & clinical cancer research : CR
ERG inhibition selectively sensitizes ERG-positive prostate cancer to radiation through DNA repair vulnerabilities and enhances response to androgen receptor inhibitors
By Moustafa A, Elsesy ME, Siebels B and 14 others.
Abstract
Background
ERG overexpression, driven by TMPRSS2-ERG gene fusion, occurs in ~ 50% of prostate cancers (PCa) and defines a molecular subtype with distinct therapeutic vulnerabilities. Radiotherapy (RT) is a cornerstone for localized and locally advanced PCa, yet substantial number of patients experience treatment failure. This study investigates whether direct ERG inhibition selectively impairs the resolution of DNA damage signaling and radiosensitizes ERG-positive PCa, providing a precision medicine strategy.
Methods
ERG-positive VCaP cells, ERG-negative DU145/BPH1 cells, ex vivo patient PCa tissue slice cultures (TSCs, n = 14 from 10 patients), and patient-derived organoids (PDOs, n = 2) were treated with ERG inhibitors (ERGi-USU, VPC-18005) or ERG siRNA ± irradiation (2-6 Gy). DNA double-strand break (DSB) repair was assessed via γ H2AX/53BP1 immunofluorescence and pEJ-GFP reporter assay. Clonogenic survival was evaluated in 2D/3D assays. Label-free quantitative LC-MS/MS proteomics identified differentially regulated pathways, validated by immunoblotting. Promoter activity was measured using GLuc-ON™ Promoter Reporter plasmids.