Abstract 5582: Interrogating the K-ras/p53 transcriptional readout for synthetic lethality applications

Abstract Some Oncogenes (Onc) are physiologically indispensable or have proven difficult to inhibit (Myc and Ras, respectively). Onc addiction, reflecting the need for specific stress adaptations (SA) to accommodate constant onc signaling, provide a novel approach to disrupt the SA producing synthetic lethality (SL). Broad’s dep map CRISPR screens (CS) suggest SA is NOT monogenic. Combinatorial consideration is unavoidable and can only be fruitful if aided by biologic insights. Genetically engineered mouse models confirmed that p53 is sufficient to facilitate full oncogenic abilities of Ras. p53 transcriptional (Tr) network is a mere 110 genes and includes many repressed targets (T) but some that retain Tr activity despite the p53 DNA binding domain mutations (mu). Retained genes (g) are being considered here as putative therapeutic Ts. Identifying indispensable g in Ras onc SA is needed for CRISPR multiplexed screen. We focused on pancreatic adenocarcinoma (PA) due to high prevalence of Ras/p53 and the poor available treatment options. We hypothesize that specific set of p53 retained Tr Ts provide the SA and this may be phenocopied in few wild type (WT) p53 PA. This would guide CS for therapeutic applications. Methods: We probed TCGA and the Broad public databases for expression of the canonical p53 Tr T in Ras & p53 double mutant PA. We reasoned that MDM2 represents the most rational internal control for reduced Tr in basal, unstimulated conditions; all g with higher Tr are scored as retained; the remaining as lost Tr. WT PA were analyzed to identify phenocopy providing additional strength to the hit. The table summarizes the findings at the different levels of scrutiny. Conclusion: Our work represents a rational biologic approach to select a rational set of SL g in the Ras/p53 interdependence circuitry. Such Ts need to be examined by CS to validate their cellular importance. Pathway analysis and considering the possible double negative inhibition of repressed Ts are additional approaches to this analysis. Citation Format: Samuel L. Schach, Farah Mazahreh, A. Mazin Safar. Interrogating the K-ras/p53 transcriptional readout for synthetic lethality applications [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 5582.