Cancer Cell Lines for Drug Discovery and Development

Abstract

Despite the millions of dollars spent on target validation and drug optimization in preclinical models, most therapies still fail in phase III clinical trials. Our current model systems, or the way we interpret data from them, clearly do not have sufficient clinical predictive power. Current opinion suggests that this is because the cell lines and xenografts that are commonly used are inadequate models that do not effectively mimic and predict human responses. This has become such a widespread belief that it approaches dogma in the field of drug discovery and optimization and has spurred a surge in studies devoted to the development of more sophisticated animal models such as orthotopic patient-derived xenografts in an attempt to obtain more accurate estimates of whether particular cancers will respond to given treatments. Here, we explore the evidence that has led to the move away from the use of in vitro cell lines and toward various forms of xenograft models for drug screening and development. We review some of the pros and cons of each model and give an overview of ways in which the use of cell lines could be modified to improve the predictive capacity of this well-defined model. Cancer Res; 74(9);

The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets

“…MSI was detected in 63/151 cases (42%; Supplementary Data 1). It has been previously noted that a higher than expected fraction of CRC cell lines are MSI, conceivably because MSI tumours can be more easily propagated in vitro 15 . We also observed that the rare hypermutator/ MSI-negative subgroup, identified in about 2% of CRC cases, is represented by three lines, HT115, HCC2998 and HT55 (ref.…”

A critical analysis of cancer biobank practices in relation to biospecimen quality

“…Pre-clinical cancer research frequently involves experiments using model systems such as cancer cell lines and animal models of disease. Cancer cell lines are accessible, inexpensive and, in some cases, represent adequate disease models (Wilding and Bodmer 2014). Concerns over the impacts of cell line cross-contamination and mis-identification are now being addressed through better cell culture practices (Geraghty et al 2014) and journal-imposed requirements for researchers to authenticate cell lines using short tandem repeat (STR) profiling (Lichter et al 2010).…”

“…Concerns over the impacts of cell line cross-contamination and mis-identification are now being addressed through better cell culture practices (Geraghty et al 2014) and journal-imposed requirements for researchers to authenticate cell lines using short tandem repeat (STR) profiling (Lichter et al 2010). However, other limitations, such as those imposed by routine cell culture systems, the consequences of long-term passaging, including loss of tumour heterogeneity, and genetic drift from genomic instability, result in cell lines incompletely representing the original tumour state within the host (LaBaer 2012;Wilding and Bodmer 2014). The growth of cancer cell lines as xenograft models provides a three-dimensional tissue environment (Wilding and Bodmer 2014), but not always one that is orthotopic (Saletta et al 2014).…”

“…However, other limitations, such as those imposed by routine cell culture systems, the consequences of long-term passaging, including loss of tumour heterogeneity, and genetic drift from genomic instability, result in cell lines incompletely representing the original tumour state within the host (LaBaer 2012;Wilding and Bodmer 2014). The growth of cancer cell lines as xenograft models provides a three-dimensional tissue environment (Wilding and Bodmer 2014), but not always one that is orthotopic (Saletta et al 2014). Xenograft models also present additional barriers, such as high cost and low-throughput capacity (Wilding and Bodmer 2014), in addition to the physiological differences between small animal models and humans (see review of Lal et al, this edition of Biophysical Reviews).…”

“…The growth of cancer cell lines as xenograft models provides a three-dimensional tissue environment (Wilding and Bodmer 2014), but not always one that is orthotopic (Saletta et al 2014). Xenograft models also present additional barriers, such as high cost and low-throughput capacity (Wilding and Bodmer 2014), in addition to the physiological differences between small animal models and humans (see review of Lal et al, this edition of Biophysical Reviews). Because of these limitations, researchers are increasingly seeking to perform pre-clinical studies using human cancer samples and associated tissue controls.…”