Speaker
Description
Radiotherapy remains a cornerstone in the treatment of brain tumors; however, its
effectiveness can be limited by intrinsic cellular resistance driven by TP53 mutations and
altered DNA repair capacity. MDM2 inhibitors such as AMG232 are designed to restore TP53
pathway activity, potentially enhancing radiosensitivity. Understanding how AMG232
influences DNA damage responses, cell-cycle regulation, gene expression, and proliferation
in TP53 wild-type and mutant brain tumor cells is essential for improving therapeutic
outcomes. The aim of this study was to enhance the effectiveness of radiotherapy by
determining whether the MDM2 inhibitor AMG232 increases radiation-induced DNA damage
and modulates repair kinetics, cell-cycle progression, gene expression, and proliferation in
TP53 wild-type and mutant brain tumor cell lines. TP53 wild-type (ONS-76 and A172) and
TP53 mutant (DAOY and U251) brain tumor cell lines were treated with AMG232 and exposed
to photon irradiation at 1 Gy and 2 Gy. DNA double-strand breaks (DSBs) were quantified
using γ-H2AX foci formation at 0.5, 2, 4, 8, 12, and 24 hours post-irradiation, with and without
drug treatment. Cell proliferation was assessed through doubling-time (DT) measurements
following incubation with AMG232 for 24, 48, and 72 hours. Cell-cycle progression and
checkpoint activation were evaluated by flow cytometry at 8, 12, 16, and 24 hours. Gene
expression analysis of TP53-related pathway markers was performed at 0.5, 4, and 24 hours.
AMG232 increased TP53 pathway activation in wild-type cell lines, resulting in elevated initial
DNA damage levels and delayed repair kinetics following irradiation. In TP53 mutant lines,
AMG232 modulated repair dynamics and altered cell-cycle distribution but to a lesser extent
than in wild-type cells. Proliferation assays showed increased growth suppression with
AMG232, particularly in TP53 wild-type cells. Gene expression analysis confirmed
upregulation of TP53-associated targets in wild-type lines, while mutant cells exhibited partial
or altered transcriptional responses. AMG232 enhances the cellular response to photon
irradiation in a TP53-dependent manner, with TP53 wild-type brain tumor cells showing the
strongest radiosensitization effects. These findings support the potential of AMG232 as a
radiosensitizing agent and highlight the importance of TP53 status in predicting treatment
response. Incorporating MDM2 inhibition may represent
| Apply for student award at which level: | PhD |
|---|---|
| Consent on use of personal information: Abstract Submission | Yes, I ACCEPT |