Abstract 4043: Stimulation of the mapk and pi3k/akt pathways in pancreatic cancer cells by polyisoprenylated cysteinyl amide inhibitors

Abstract

Abstract Pancreatic cancer is the third deadliest cancer with a 5-year survival rate of less than 10%. Over 90% of reported cases are driven by KRAS mutations. KRAS signals through the MAPK and PI3K pathways. Targeting mutant KRAS has been a decades-long challenge until recently whereby drugs that react with specific mutant proteins have been developed. Polyisoprenylated cysteinyl amide inhibitors (PCAIs) are potential anticancer agents with an alternative design strategy targeting polyisoprenylation-dependent processes of hyperactive mutant or overexpressed G-proteins. The effect of PCAIs on the viability and downstream mediators of KRAS signaling was determined on PANC-1 and MIAPaCa-2 cells. Of the 16 different analogs tested, NSL-YHJ-2-45 and NSL-YHJ-2-27 were the most potent with EC50 values of 3.6 and 3.8 against PANC-1 cells, respectively. For MIAPaCa-2 cells, NSL-YHJ-2-27 was the most potent with an EC50 value of 2.2. Western blotting analysis of PCAIs-treated PANC-1 cells revealed that phosphorylated BRAF, MEK 1/2, ERK 1/2 and p90RSK increased by 64, 129, 152 and 79%, respectively, while phosphorylated CRAF levels decreased by 27%. Moreover, monomeric G-proteins, CDC42, RHOA and RAC 1/2/3 protein levels decreased by 20, 58 and 13%, respectively. NSL-YHJ-2-27 (5 µM) also increased the levels of pAKT (Ser 473) and pAKT (Thr 308) by 72 and 192%, respectively. When MIAPaCa-2 cells were treated with 0-5 µM NSL-YHJ-2-27, MEK 1/2, ERK 1/2 and p90RSK phosphorylation increased by 78, 270 and 260%, respectively. However, at 5 µM NSL-YHJ-2-27, there were no significant changes in protein levels of the monomeric G proteins RAC 1/2/3 and RHOA, but protein levels of CDC42 increased by 132%. NSL-YHJ-2-27 (5 µM) increased the levels of pAKT (Ser 473) and pAKT (Thr 308) of MIAPaCa-2 cells by 97 and 82%, respectively. The results indicate the effect of PCAIs on the phosphorylation of important kinases involved in MAPK and AKT pathways. These effects on these signaling pathways strongly indicate the potential of the PCAIs against RAS-driven cancers. Citation Format: Kweku Ofosu-Asante, Jassy M. Lazarte, Amarendar G. Burra, Nazarius S. Lamango. Stimulation of the mapk and pi3k/akt pathways in pancreatic cancer cells by polyisoprenylated cysteinyl amide inhibitors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4043.