Abstract
Lung cancer is the leading cause of cancer-related deaths in the USA and worldwide. Yet, about 95% of new drug candidates validated in preclinical phase eventually fail in clinical trials. Such a high attrition rate is attributed mostly to the inability of conventional two-dimensionally (2D) cultured cancer cells to mimic native three-dimensional (3D) growth of malignant cells in human tumors.To ascertain phenotypical differences between these two distinct culture conditions, we carried out a comparative proteomic analysis of a membrane fraction obtained from 3D- and 2D-cultured NSCLC model cell line NCI-H23. This analysis revealed a map of 1,166 (24%) protein species regulated in culture dependent manner, including differential regulation of a subset of cell surface-based CD molecules. We confirmed exclusive expression of CD99, CD146 and CD239 in 3D culture. Furthermore, label-free quantitation, targeting KRas proteoform-specific peptides, revealed upregulation of both wild type and monoallelic KRas4BG12C mutant at the surface of 3D cultured cells.In order to reduce the high attrition rate of new drug candidates, the results of this study strongly suggests exploiting base-line molecular profiling of a large number of patient-derived NSCLC cell lines grown in 2D and 3D culture, prior to actual drug candidate testing.
Highlights
Lung carcinoma is the deadliest cancer in the United States and worldwide [1]
In order to reduce the high attrition rate of new drug candidates, the results of this study strongly suggests exploiting base-line molecular profiling of a large number of patient-derived non-smallcell lung cancer (NSCLC) cell lines grown in 2D and 3D culture, prior to actual drug candidate testing
To better understand and standardize results obtained in the preclinical phase, it is of prime interest to better characterize and compare molecular phenotypes of lung cancer cells grown in 2D- and 3D-culture
Summary
Lung carcinoma is the deadliest cancer in the United States and worldwide [1]. In 2019, the American Cancer Society reported 142,670 deaths from lung cancer in the United States. Adherent two-dimensional (2D) in vitro cultures of human cancer cell line are the mainstay preclinical testing model used in lung cancer drug development and discovery [6]. There is an outstanding and unmet need for better characterization of preclinical lung cancer models to facilitate development of more effective predictive therapeutic biomarkers involved in molecular pathways driving lung cancer tumorigenesis [11] This approach creates a pathway towards the development of a preclinical atlas depicting the molecular profiles of cell lines grown in 2D vs 3D, information that is sorely needed to accurately monitor drug development. The differential molecular phenotype of a NSCLC cell line membrane proteome grown in 2D- vs. 3D-culture is still missing
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