Systematic Evaluation of Combination Strategies with Rezatapopt in p53 Y220C–Mutant Cancer Models

Abstract Rezatapopt (PC14586), a first-in-class Y220C-selective p53 reactivator, demonstrates single-agent clinical efficacy; however, combinatorial strategies may enhance clinical outcomes. Here, we evaluated rezatapopt in combination with standard-of-care agents (chemotherapy and bevacizumab), murine double minute 2 (MDM2) inhibitors, and a library of FDA-approved compounds. While chemotherapy, bevacizumab, and MDM2 inhibitors showed in vivo efficacy, a high-throughput screen identified the phosphoinositide 3-kinase (PI3K)/ Protein Kinase B (AKT)/mechanistic target of rapamycin (mTOR) and mitogen-activated protein kinase pathways as top synergistic candidates. Validation confirmed that PI3Kα inhibition synergized with rezatapopt to deepen apoptosis and tumor growth inhibition in xenograft models. Thus, PI3K/mTOR pathway inhibition may represent a clinically actionable, conserved p53-reactivation vulnerability across diverse histologies harboring a TP53 Y220C mutation.