Abstract C168: Developing lung adenocarcinoma cell lines to mitigate lung cancer health disparities

Abstract

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/AAs. 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 of which are derived from White and Asian patients. Moreover, only 6 of the 30 cell lines are derived from patients with LUAD. We are in the process of deriving more LUAD cell lines from B/AA patients as well as alveolar epithelial cell lines in order to study the development of LUAD. In addition, we are creating a collection of multiple independent isogenic cell line variants from an existing lung cancer cell line NCI-H23. 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/Cas-9 genome- based editing to replace the KRASG12C mutation with KRASG12V, KRASG12D, KRASG12A, and KRASG13C. We have derived multiple independent cell lines for most mutations. We are in the process of performing whole genome sequencing of these cell lines to exclude any off-target effects that may have arisen from the CRISPR/Cas-9 engineering. In addition, we will carry out whole genome RNA sequencing to assess the effect of the engineering and/or KRAS mutation switching. As a control, we are also sequencing 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) and other drugs on cell lines bearing these KRAS mutations. PCAIs were developed to target cells carrying mutant KRAS. 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. Citation Format: Sofia A. Lugo, Christopher Leon, Matthew A. Gladstone, Chunli Yan, Daniel J. Mullen, Pablo E. Puente, Kweku Ofosu-Asante, Justin K. Mensah-Mamfo, Kyle R. Phillips, Yong Huang, Nazarius S. Lamango, Ite A. Offringa. Developing lung adenocarcinoma cell lines to mitigate lung cancer health disparities [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C168.