Pharmacologic Inhibition of RBBP4/p300-mediated Homologous Recombination Activity Enhances Glioblastoma Sensitivity to Temozolomide
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ID: 315423
2026
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Abstract
Abstract Background Upstream regulators of the homologous recombination (HR) repair pathway are promising targets for overcoming temozolomide (TMZ) resistance. We investigated whether pharmacologic inhibition of RBBP4/p300-mediated HR activity by CCS1477 or NEO2734 sensitizes GBM to TMZ. Methods Lentiviral-mediated shRNA was used to silence RBBP4 and EP300 (p300). A fluorescence-based multiplex flow-cytometric host cell reactivation assay (FM-HCR) was used to measure DNA repair activity, while TMZ-induced DSBs were assessed using comet assay and γ-H2AX foci formation. Cytotoxicity was monitored using an Incucyte device, and survival analysis was performed to evaluate efficacy in orthotopic tumor models. Drug distribution was assessed using liquid chromatography–mass spectrometry (LC-MS/MS) and H3K27Ac immunofluorescence (IF) for target inhibition. Promoter occupancy was determined using chromatin immunoprecipitation (ChIP). Results GBM PDX tumors with high RBBP4 expression showed elevated levels of six HR genes (RAD51, RAD50, BRCA1, BARD1, BRIP1, and FIGNL1), with RAD51 and BRIP1 correlating strongly with RBBP4 and p300. Silencing RBBP4 or p300 decreased HR and MMEJ activity, and delayed repair of TMZ-induced DSBs. CCS1477 and NEO2734 suppressed RAD51 and MYC in a concentration-dependent manner, prolonged γ-H2AX foci, and enhanced TMZ sensitivity. Both compounds inhibited H3K27Ac and were detectable in orthotopic tumors by LC-MS/MS, and significantly extended survival alone and in combination with TMZ. Conclusion These findings suggest that the RBBP4/p300-axis is a key regulator of HR-mediated repair of TMZ-induced DSBs, and inhibition by either CCS1477 or NEO2734 may be beneficial as monotherapy but further studies are needed to determine the benefit of combining these agents with TMZ.
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| Authors | Josephine Mapunda, Daniel J. Laverty, Faisal Aziz, An Le, Junita Sangare, Lin Zhang, Zachary D. Nagel, Jarrod B. French, Jann N Sarkaria, Gaspar J. Kitange |
| Journal | Neuro-Oncology Advances |
| Year | 2026 |
| DOI |
10.1093/noajnl/vdag141
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| URL | |
| Keywords | Keywords not found |
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