Abstract 2680: PCAI-induced phosphorylation of MAP kinase pathway enzymes is associated with cell death of black American lung adenocarcinoma cell line NCI-H23

Abstract

Abstract Lung cancer is a leading cause of cancer-related mortality accounting for 23% of cancer deaths in the US. Non-small cell lung cancer (NSCLCs) comprises 84% of all lung cancer cases, and of these, 40% are lung adenocarcinoma (LUAD). Moreover, black Americans are underrepresented in scientific clinical trials but have a lung cancer incidence rate that is 37% higher than their white counterparts. To address this disparity and lack of effective treatment options, we determined the potency of polyisoprenylated cysteinyl amide inhibitors (PCAIs) on cell viability and its effects on KRAS and its downstream mediators in NCI-H23, a black American cell line that harbors a KRAS mutation. Among the 17 PCAIs that were tested, compound NSL-YHJ-2-27 showed the most potency with an EC50 of 2.7 µM. Western blot analysis was performed to determine the effect of the PCAIs on the levels of Mitogen-Activated Pathway Kinase (MAPK)-related proteins. After 48 h of exposure to 5 μM of NSL-YHJ-2-27, we observed increases of 150, 64.5, and 77% in phosphorylation levels of ERK1/2, MEK1/2, and 90RSK. While the particular 90RSK enzymes whose phosphorylation is/are elevated are not known at this time, 90RSK 3 and 4 are known to be proapoptotic. These findings suggest that the PCAIs may be used to target cancers with KRAS mutations that currently lack effective therapies. In the future, we will use a collection of isogenic cell lines to examine the potency of the PCAIs in LUAD driven by other RAS and related monomeric G-proteins, epidermal growth factors, and their receptors as well as RAS-GAPs. Therapies emanating from these studies have the potential to contribute to mitigating the lung cancer therapeutic inequities. Keywords: Polyisoprenylated Cysteinyl Amide Inhibitors (PCAIs), Mitogen Activated Pathway Kinases (MAPK), KRAS, Lung Adenocarcinoma (LUAD), Non-small cell lung cancer (NSCLCs) Citation Format: Matthew D. Gregory, Nada Tawfeeq, Jassy M. Lazarte, Yonghao Jin, Pablo Puente, Nadine Belony, Ite A. Offringa, Yong Huang, Nazarius S. Lamango. PCAI-induced phosphorylation of MAP kinase pathway enzymes is associated with cell death of black American lung adenocarcinoma cell line NCI-H23 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2680.