Lung cancer, which remains a major cause of mortality worldwide, is a histologically diverse condition and demonstrates substantial phenotypic and genomic diversity among individual patients, manifesting as both intertumoral and intratumoral heterogeneity. This heterogeneity has made it difficult to develop lung cancer models. Two-dimensional (2D) cancer cell lines have been used to study genetic and molecular alterations in lung cancer. However, cancer cell lines have several disadvantages, including random genetic drift caused by long-term culture, a lack of annotated clinical data, and most importantly, the fact that only a subset of tumors shows 2D growth on plastic. Three-dimensional models of cancer have the potential to improve cancer research and drug development because they are more representative of cancer biology and its diverse pathophysiology. Herein, we present an integrated review of current information on preclinical lung cancer models and their limitations, including cancer cell line models, patient-derived xenografts, and lung cancer organoids, and discuss their possible therapeutic applications for drug discovery and screening to guide precision medicine in lung cancer research. Altogether, the success rate of generating lung cancer organoids must be improved, and a lung cancer organoid culture system is necessary to achieve the goal of designing an individualized therapeutic strategy for each lung cancer patient.
