Abstract 5605: Development of a novel protein phosphatase 2A (PP2A) activator, PPA27, as a potential therapeutic for melanoma

Abstract Protein phosphatase 2A (PP2A) is a vital serine/threonine phosphatase acting as a tumor suppressor, often inactivated in melanoma and other cancers. This study builds upon our initial findings on the PP2A activators PPA24 and PPA27, focusing on extended in vitro and in vivo evaluations to assess PPA27's therapeutic potential against melanoma. In our previous work, both compounds demonstrated selective cytotoxicity in melanoma cell lines. Here, we further characterize PPA27’s efficacy across five melanoma cell lines (SK-MEL-2, SK-MEL-28, A375, Mel1241, and 451Lu), showing IC50 values ranging from 3.45-8.94 µM, with consistent effectiveness regardless of BRAFV600E mutation status. Mechanistic analyses revealed that PPA27 induced apoptosis in a dose-dependent manner as confirmed by increased caspase-3/7 activation and PARP cleavage. Notably, PPA27 treatment significantly downregulated phosphorylated ERK1/2, particularly in BRAFV600E-positive A375 cells, suggesting differential modulation of MAPK pathways in mutant and wild-type contexts. To validate these findings in vivo, the efficacy of PPA27 was assessed in xenograft melanoma mouse models. The compound significantly reduced tumor growth compared to control without any apparent systemic toxicity. Additionally, pharmacokinetic and ADMET analyses indicate that PPA27 possesses excellent bioavailability, stability, and metabolic properties, supporting its potential for clinical translation. Furthermore, combinatorial studies suggest that PPA27 enhances the efficacy of existing BRAF inhibitors, potentially addressing drug resistance issues in melanoma therapy. These findings highlight PPA27's robust therapeutic potential and provide new insights into its mechanism of action. In conclusion, our expanded investigation establishes PPA27 as a promising candidate for melanoma treatment, warranting further preclinical studies before consideration for clinical trials targeting both BRAF-mutant and wild-type melanoma subtypes. Citation Format: Hannah Johnson, Amandeep Singh, Asif Raza, Satya Narayan, Arun K. Sharma. Development of a novel protein phosphatase 2A (PP2A) activator, PPA27, as a potential therapeutic for melanoma [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 5605.