Patient-derived cell line, xenograft and organoid models in lung cancer therapy

Abstract

Lung cancer accounts for most cancer-related deaths worldwide and has an overall 5-year survival rate of ~15%. Cell lines have played important roles in the study of cancer biology and potential therapeutic targets, as well as pre-clinical testing of novel drugs. However, most experimental therapies that have cleared preclinical testing using established cell lines have failed phase III clinical trials. This suggests that such models may not adequately recapitulate patient tumor biology and clinical outcome predictions. Here, we discuss and compare different pre-clinical lung cancer models, including established cell lines, patient-derived cell lines, xenografts and organoids, summarize the methodology for generating these models, and review their relative advantages and limitations in different oncologic research applications. We further discuss additional gaps in patient-derived pre-clinical models to better recapitulate tumor biology and improve their clinical predictive power.

Keywords: 3D culture; Lung cancer; cell line; organoid; patient-derived models; preclinical models; xenograft.

Figure 1

Schematic of CRISPR-Cas9 knockout system. PAM, protospacer adjacent motif; NHEJ, non-homologous end joining; PDX, patient-derived xenograft.

Figure 2

CCLE RNA-seq data on TTF1 and TP63 expression in lung adenocarcinoma and lung squamous cell carcinoma. TTF1, Transcription Termination Factor 1; TP63, Tumor Protein P63. Raw data obtained from https://portals.broadinstitute.org/ccle, assessed on Sep 3rd, 2019.

Figure 3

Methodology and applications of preclinical patient-derived lung cancer models. Solid lines represent greater compatibility between models and applications. Dashed lines represent lesser compatibility between models and applications. EBUS, endobronchial ultrasound.