Abstract 666: ASTX295 engages p53-mediated apoptosis and an inflammatory response in patient derived mesothelioma explants

Abstract

Abstract Mesothelioma is a universally lethal, rare cancer caused by asbestos that is lacking effective targeted treatments, particularly in the relapsed setting. P53 is predominantly wildtype (WT 83%) but is likely restrained by MDM2 particularly in the context of 9p21 deletion, a common, clonal somatic event affecting around half of all mesotheliomas that results in deletion of the MDM2 suppressor ARF. 9p21 deletion is also associated with a cold, immunosuppressed microenvironment. Unleashing p53WT by inhibiting its interaction with MDM2 has therapeutic potential in mesothelioma. To test this hypothesis, we employed live patient derived explants (PDEs) as a model that reflects the genomic inter-patient heterogeneity of mesotheliomas, and harbours an intact tumour microenvironment. Between August 2017 and April 2021 a total of 71 patients were consented prior to extended pleurectomy decortication, and PDEs were harvested at the time of surgery. PDEs were then cultured and treated with ASTX295, an inhibitor of p53-MDM2 interaction, using two concentrations (0.5 and 1 micromolar) and two timepoints (48 and 72 hours). PDEs passing quality control were subjected to spatial profiling using multiplex immunofluorescence microscopy. PDEs harbouring p53WT showed ASTX295-induced p21 (CDK1A) upregulation, which correlated with induction of apoptosis (p=0.04). PDE rank-order sensitivity was conserved across different doses and exposure-times. Transcriptome analysis confirmed ASTX295 induced p53 pathway activation in conjunction with a pro-inflammatory phenotype; both of which were absent in one PDE harbouring an inactivating p53 single nucleotide variant. Constitutive epithelial mesenchymal transition (EMT) was enriched in responding PDEs, as well as MDM2 inhibitor sensitive mesothelioma cell lines. 9p21 deletion (revealed by exome sequencing) was detected in both responding and non-responding PDEs. In summary, inhibition of MDM2-P53 interaction triggers robust p53 activation and a pro-inflammatory phenotype, which is potentiated in EMT enriched mesothelioma PDEs. ASTX295 is currently under clinical investigation (NCT03975387). Citation Format: Dean Anthony Fennell, Joanna Dzialo, Jan Rogel, Daniel Faulkner, Nada Nusrat, Aleksandra Bzura, Kudzayi Kutywayo, Peter Wells-Jordan, Charlotte Poile, Andrea Biondo, Martin Sims, Apostolos Nakas, Jin-Li Luo, Min Zhang, Maria Ahn. ASTX295 engages p53-mediated apoptosis and an inflammatory response in patient derived mesothelioma explants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 666.