Abstract 4691: Concurrent EGFR inhibition and radiotherapy potentiates radioresistance in <i>TP53</i>-mutated endometrial cancer

Abstract Introduction: Endometrial cancers (EC) that harbor TP53 mutations portend a worse clinical prognosis. EGFR inhibition has emerged as a potential radio-sensitizing strategy, particularly in NSCLC and HNSCC, however, its effect in TP53-mutated tumors is mixed. As emerging data demonstrates that TP53 mutations may confer radioresistance in endometrial cancer, we explored the role of EGFR inhibition as a novel radio-sensitizing strategy in this disease site. Methods: To evaluate the effect of EGFR inhibition on radiation response, we employed the parental EC cell line, Hec1B (TP53 R248Q mutation). Cells were treated with increasing doses of the EGFR inhibitor, erlotinib, while concurrently exposed to varying doses of radiation. Cells were treated for 48 hours with erlotinib, and viability was assessed with CellTiter-Glo. IC50 values were determined using GraphPad Prism software. Drug synergy was determined using the Bliss independence model. A MeanR test was also used to compare the predicted response (additive) of the Bliss model to our data. All experiments were carried out in triplicate. Results: The IC50 value of erlotinib alone was 14.4uM. At 6Gy of radiation, the IC50 of erlotinib was 23.1uM. Per the Bliss independence model, erlotinib was not observed to have a synergistic effect with radiotherapy. However, the MeanR test of the deviation from additivity demonstrated antagonism with an F-statistic of 6.46, p = 0.02. Conclusion: Concurrent use of erlotinib potentiates radioresistance. Novel therapeutic and sequencing radio-sensitizing strategies remain to be elucidated in TP53 mutated EC. Citation Format: Gabriella Smith, Aaron Petty, Roberto Vargas. Concurrent EGFR inhibition and radiotherapy potentiates radioresistance in TP53-mutated endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4691.