Abstract 6827: Developing lung adenocarcinoma cell lines to test new drugs and mitigate lung cancer health disparities

Abstract Lung cancer continues to be the number one cause of cancer-related deaths worldwide and remains a prominent source of cancer health disparities. Black/African American (B/AA) males exhibit a 12% higher lung cancer incidence rate and a 15% higher lung cancer death rate when compared to white males. Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer in all ethnic/racial groups, including B/AA individuals. To further examine this phenomenon, we want to create a collection of lung cancer cell lines that would be useful for molecular studies of lung cancer development, progression, development of new targeted therapies, and pre-clinical drug testing. After reviewing the literature (Leon et al. 2023, Frontiers in Oncology, Vol. 13, p. 1187585, 2023), we identified only 30 unique B/AA cell lines out of ∼800, the majority being from White and Asian patients. Moreover, only 6 of the 30 cell lines are LUAD. In order to mitigate this disparity, we are creating a collection of multiple independent isogenic cell line variants from the existing NCI-H23 lung cancer cell line. NCI-H23 was derived from a B/AA male LUAD patient and harbors a KRASG12C heterozygous mutation. G12C is the most common KRAS mutation in LUAD (∼40% of KRAS mutations) followed by G12V (∼20%), G12D (∼15%), G12A (∼10%), and G13C (∼6%). We used CRISPR/Cas9 genome-based editing to replace the KRASG12C mutation with KRASG12V, KRASG12D, KRASG12A, and KRASG13C. We have derived independent cell lines for most mutations. We have performed whole genome sequencing of these cell lines to assess possible off-target effects that may have arisen from the CRISPR/Cas9 engineering. In addition, we will carry out whole genome RNA sequencing to examine the effect of the engineering and/or KRAS mutation switching. As a control, we have sequenced the genomes and transcriptomes of three monoclonal cell lines we derived from NCI-H23 cells, to determine what variability ensues with the derivation of monoclonal lines, since that is required to obtain the CRISPR/Cas9 edited cells. We will use this collection of cell lines to study the efficacy of polyisoprenylated cysteinyl amide inhibitors (PCAIs). PCAIs were developed in the Lamango lab to target and suppress hyperactivities of G-proteins in cancers driven by mutant KRAS. We will test PCAIs alone, in comparison and in combination anti-KRAS drugs on the new cell lines bearing diverse KRAS mutations. Our efforts will provide new cell lines to study lung adenocarcinoma in B/AA subjects addressing a key shortcoming and disparity in the lung cancer research toolkit, thereby facilitating the testing of potential new therapies such as PCAIs in an African ancestry background. Citation Format: Kweku Ofosu-Asante, Sofia Lugo, Bianca Dal Bo, Matthew A. Gladstone, Chunli Yan, Daniel J. Mullen, Kyle R. Philips, Benjamin J. Ryder, Yong Huang, Ite A. Offringa, Nazarius S. Lamango. Developing lung adenocarcinoma cell lines to test new drugs and mitigate lung cancer health disparities [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 6827.