Abstract 1124: Mining the Kras-p53 mutational interface for synthetic lethality (SL) in pancreatic adenocarcinoma (PA)

Abstract Kras activating mutations are frequent in cancer but are insufficient alone for full malignant transformation. Mutations in the tumor suppressor (TSG) p53 cooperate with mutant Kras and permit full display of oncogenic Ras, both in clinical cases and in experimental models of Kras tumorigenesis. Interestingly, p53 mutations almost never fully abrogate its function, suggesting to us a possible essential role for the (either directly or indirectly) retained transcriptional targets within the p53 network. The phenomenon of oncogene addiction may be the result of this rigid but sufficient TSG output providing adaptations to constant oncogene signaling. It is also plausible that each mutation might provide different adaptations and therefore be differentially selected for in various cases. Drugging the dependency on this adaptation machinery provides an opportunity for SL sparing normal cells. This approach is especially valuable given the limited therapeutic impact of available Kras inhibitors (in scope or in potency). We have shown that specific mutations in p53 with their unique transcriptional lesions cooperate with various Kras mutants in tissue-specific manner. In this work we provide a broader and comparative assessment in PA. We hypothesize that frequency of the top 8 p53 mutational hotspots in PA is non-random with recurring comparable frequencies across independent public datasets (project GENIE, MSK and TCGA). Our work included 4 Kras PA mutants. Results: Table reports on the frequency of respective mutational pairs. Conclusion: The available cases in TCGA were limited in number. In the 2 more comprehensive datasets, the frequency of certain pairs between Kras and p53 is remarkably close suggesting a mechanistic justification. For SL considerations, therefore, one needs to examine the transcriptional spectra within defined pairs of Kras-p53 to nominate the appropriate genes for multiplexed gene editing experiments and inform drug discovery. Citation Format: Nishanth Thalambedu, Nadia Safar, Ahmad Mazin M. Safar. Mining the Kras-p53 mutational interface for synthetic lethality (SL) in pancreatic adenocarcinoma (PA) [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 1124.