Synergistic effect of MDM2 inhibitors and radiotherapy in endometrial cancer

Endometrial cancer (EC) is the most common type of gynecologic malignancy in the United States, with over 69,120 new cases expected in 2025. The total number of mortalities surpasses that of ovarian cancer. Despite our ability to identify different biological clusters of EC, we have yet to understand the functional impact of key genomic alterations associated with varying prognoses and exploit this knowledge for therapeutic benefits. Our overarching goal is to understand how genomic alterations impact radiotherapy response in EC, and whether manipulation of these signaling pathways could be utilized as a radio-sensitization strategy. Given that TP53-mutated ECs portend the worst prognoses and seem to benefit from escalation of therapy above that of radiotherapy alone, we first focused our attention on understanding the impact of this genomic aberration on radiation response. Using high-throughput in vitro profiling, genomic manipulation, and in vivo studies, we demonstrated that p53 signaling plays a significant role in the radiotherapy response in EC, thus providing a biological rationale for observed clinical trial findings. We also leveraged this same finding to test a therapeutic approach driving p53/p21 signaling using murine double minute-2 (MDM2) inhibitors, subsequently demonstrating synergism with radiation. Thus, MDM2 inhibitors could be considered as a novel radiosensitizing approach for EC.