Abstract 356: Rezatapopt and KRAS inhibitors for the treatment of TP53 Y220C and <i>KRAS</i> mutant cancers.

Abstract Background: TP53 and KRAS are two important genes involved in cancer development. KRAS is involved in cell growth and division, and KRAS mutant cancers often do not respond to treatments. P53 is a transcription factor that regulates cell cycle and prevents tumor formation. Cancer cells with TP53 mutations can evade p53-mediated tumor suppression. Combined TP53/KRAS mutations are associated with drug resistance and worse prognosis. Rezatapopt is a small molecule reactivator of p53 Y220C protein. It binds the mutant protein and stabilizes p53 structure in the wild-type conformation restoring its functions. TP53 Y220C is present in approximately 1% of all solid tumors. We hypothesized that rezatapopt in combination with standard or targeted therapies enhances treatment response in TP53 Y220C/KRAS altered tumors. Methods: We used three TP53 Y220C cell lines that also had KRAS G12D or Q61H mutations to analyze the effects of drug combinations. Following a high-throughput screening with 23 drugs using an ATP quantification-based cell viability assay, we selected 6 agents and confirmed the results using sulforhodamine B (SRB) assay. We used Chou-Talalay and Bliss methods to calculate IC50 and combination index. We analyzed the effect of rezatapopt in combination with pan-RAS inhibitors on long-term viability of treated cells by colony formation assay. In vivo antitumor activity was assessed by objective response and event-free survival (as defined by time to tumor doubling) per PDXNET metrics. Results: Rezatapopt was synergistic with multiple chemotherapeutic and targeted therapy agents. SRB assay showed that both MRTX1133 (KRAS G12D inhibitor) or daraxonrasib (RMC-6236, pan-RAS inhibitor) were synergistic with rezatapopt in two TP53 Y220C and KRAS G12D cell lines. We generated a patient-derived xenograft model from a patient with colorectal cancer bearing TP53 Y220C and KRAS G12A mutations, and treated the model with rezatapopt (100 mg/kg, QD, PO), daraxonrasib (25 mg/kg, QD, PO), or the combination. Four out of 5 rezatapopt + daraxonrasib combination-treated tumors regressed greater than 30% from baseline by day 22 while only 1 out of 5 tumors treated with either single agent regressed by day 22. Event-free survival was significantly longer for combination-treated mice compared to mice treated with daraxonrasib alone (p=0.013) or rezatapopt alone (p=0.016). Conclusion: Rezatapopt combined with KRAS inhibition increased antitumor activity. Further studies are needed to understand the mechanism of synergy. Citation Format: Argun Akcakanat, Ecaterina E. Dumbrava, Kurt W. Evans, Ran Zhang, Ming Zhao, Amber Kennon, Xiaofeng Zheng, Stephen M. Scott, Erkan Yuca, Gabriela Raso, Elisabeth K. Kong, Yasmeen Rizvi, David Hong, Masha V. Poyurovsky, Guillermina Lozano, Anil Korkut, Funda Meric-Bernstam. Rezatapopt and KRAS inhibitors for the treatment of TP53 Y220C and KRAS mutant cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 356.