Abstract 7508: Transcriptomic analysis of polyisoprenylated cysteinyl amide inhibitors treatment of pancreatic and breast cancer reveals changes in apoptotic and angiogenic factors

Abstract The aggressive nature of KRAS-driven cancers and the lack of effective targeted therapies makes them extremely challenging to manage. The polyisoprenylated cysteinyl amide inhibitors (PCAIs) were designed to mimic the polybasic C-terminal hypervariable (HVR) region of KRAS and related proteins. The HVR and polyisoprene modifications are essential for their functional localization. Disrupting the polyisoprenylation-dependent interactions abrogates RAS signaling interactions, affording opportunities for controlling hyperactive G-proteins in cancers. Previous studies have demonstrated the effectiveness of PCAIs against cancer-progression phenomena various cancer cell lines. Hence, we determined the effect of the PCAIs on the gene expression in PANC-1, MIA PaCa-2 and MDA-MB-231 cells, to better understand biological responses elicited by cancer cells on exposure to PCAIs at gene level. Following 3 µM NSL-YHJ-2-27 treatment of MIA PaCa-2 cells, total RNA was extracted, sequenced and analyzed using Partek Flow. DESeq2 tool was used to analyze a total of 88 genes that were significantly differentially expressed. Out of the 88 genes, 85 were upregulated and 3 downregulated. Notable genes such as tumor suppressor gene, suppressor of cytokine signaling 1 (SOCS1) and autophagy-related protein 9 (ATG9L) were significantly upregulated by 2-fold and 3-fold, respectively. Moreover, treatment with 3 µM NSL-AB-51 of both PANC-1 and MDA-MB-231 cells resulted in 9 and 28 genes, respectively, being differentially expressed. The gene endothelin-1 (EDN1) which promotes cell proliferation, survival and neovascularization was significantly downregulated by one-fold in PANC-1 cells. Genes such as BCL-2 binding component 3 (BBC3) that has been shown to promote apoptosis and angiopoietin-like 4 (ANGPTL4) that inhibits tumor angiogenesis were significantly upregulated by 2-fold and 4-fold, respectively. These effects on the transcriptome strongly corroborate the phenotypic characteristics of the PCAIs against cell viability and proliferation, migration, invasion and angiogenesis and offers more opportunities to further understand and develop the PCAIs as potential agents to treat KRAS-driven cancers. Citation Format: Kweku Ofosu-Asante, Amarender Burra, Jahnissi Odoom, Joshua Ablordeppey, Nazarius S. Lamango. Transcriptomic analysis of polyisoprenylated cysteinyl amide inhibitors treatment of pancreatic and breast cancer reveals changes in apoptotic and angiogenic factors [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 7508.