An MDM2 inhibitor (JNJ-26854165) was nominated as an effective drug in treatment for RT-resistant BC cell lines (R2 = 0.43, p value <0.01) in our novel radiosensitizer screen. Differential gene expression and pathway analysis in non-overlapping p53 WT BC cell lines treated +/-RT identified apoptosis, cell cycle, and p53 signaling as the top pathways induced in p53 WT cell lines by RT. MDM2 was significantly overexpressed after RT compared to no RT in p53 WT cells. Cell growth was decreased by MDM2 inhibition with navtemadlin and alrizomadlin in p53 WT cells (IC50s: 264-592nM) and not in p53 MT cells (IC50s >10μm). MDM2 inhibition radiosensitized p53 WT cells (rERs: 1.81-2.85) but not p53 MT cells (rERs: 1.00-1.03).These results demonstrate the combination of RT and MDM2 inhibition may be an effective therapeutic strategy in patients with p53-wild type breast cancer, regardless of hormone receptor status.