Abstract B028: Synthetic lethality (SL) for pancreas cancer (PC) therapy: ‘Reading between the lines’ of the p53 transcriptional (Tr) readout

Abstract Some Oncogenes (Onc) are physiologically indispensable (Myc) or have proven difficult to inhibit (Ras). SL is an attractive novel approach to drug such Onc. The Broad’s DepMap CRISPR screen (CS) suggests that SL is NOT monogenic for Ras, therefore, identifying indispensable multi-genic signature is needed for SL confirmation in CS. Genetically engineered mouse models revealed that mutated (mu) p53 leads to full oncogenic Ras transformation. We had interrogated TCGA and Broad PC with Kras12V and hotspot mu-p53 for the 110 p53 Tr genes. Targets (T) that retain Tr activity are putative SL candidates. p21 was noted ubiquitously and is investigated here due to its combined cell cycle (CC) inhibition and antiapoptotic properties. Attenuated—yet sufficient—p21 may allow Kras-driven PC to exist. Functional WTp53 produces higher p21 levels disrupting transformation until a phenocopy emerges to alter the CC accommodating mut Kras. We hypothesize that p21 is pivotal in PC carcinogenesis attenuating the CC activity and preventing apoptosis. This will be reflected in Tr retention of p21 in larger datasets; lack of p21 homologous deletions, and comparable levels of CC activity in all PC cases, reflected by Ki-67 and PCNA. We also examine the possibility that age or p14 mediate of the phenocopy in WTp53 cases. Lastly, we examine the possibility that DREAM CC Tr controllers provide p21’s role in cases <MDM2. Methods: We used TCGA and the Broad databases to extract Tr levels of p21 in any mut-Ras PC, including all mut- and WT-p53 PC. We compared Tr output to that of MDM2 in an intra-case-controlled manner. MDM2 represents the most rational internal control for reduced Tr in basal, unstimulated conditions. We also extracted Tr values for Ki-67 and PCNA as CC metrics. WT PC were analyzed to confirm a phenocopy phenomenon and strengthen a gene’s rank for CS. Cases were grouped into 3 subsets based on comparison to MDM2 (>, within 1, or <1). Results: p21 had Tr level < 1 point of MDM2 only in 4/30 Broad cases; 7/44 TCGA cases. CC as reflected by median KI-67 levels were: [5.9, 5.4. 5.9]; PCNA: [7.4, 7.8, 8] in the Broad. In TCGA: Ki-67 [-0.48, -0.11, 1.39]; PCNA [-0.12, 0.34, -0.2] (p=NS). Though p14 deletions and truncating mutations were common, this was noted in overlapping % for WT- or mut-p53. Age distribution was similarly indifferent. DREAM components were subject to genomic alterations and are Tr active suggesting a contributory role in PC. Conclusion: We represent a rational biologic approach to select SL candidates for Ras driven PC. p21 in addition to other CC inhibitors (e.g., DREAM) seem to play existential role in Ras PC and represent a valid target for CS or other therapeutic interventions such as added CC inhibition (CDKi or hydroxyurea), or mitogens to drive in the opposite direction (e.g., insulin). Citation Format: Farah Mazahreh, A. Mazin Safar. Synthetic lethality (SL) for pancreas cancer (PC) therapy: ‘Reading between the lines’ of the p53 transcriptional (Tr) readout [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B028.