Cell line-based platforms to evaluate the therapeutic efficacy of candidate anticancer agents

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Abstract

Efforts to discover new cancer drugs and predict their clinical activity are limited by the fact that laboratory models to test drug efficacy do not faithfully recapitulate this complex disease. One important model system for evaluating candidate anticancer agents is human tumour-derived cell lines. Although cultured cancer cells can exhibit distinct properties compared with their naturally growing counterparts, recent technologies that facilitate the parallel analysis of large panels of such lines, together with genomic technologies that define their genetic constitution, have revitalized efforts to use cancer cell lines to assess the clinical utility of new investigational cancer drugs and to discover predictive biomarkers.

Key Points

  • Human tumour-derived cell lines have historically had a very important role in the discovery and development of new cancer therapeutics.

  • The National Cancer Institute 60 (NCI60) platform, which introduced the concept of high-throughput cell-based profiling, was crucial not only to the development of technologies that are still being used in various high-throughput discovery platforms, but also to the discovery of several agents that have subsequently been found to demonstrate therapeutic efficacy.

  • Subsequently developed genomic analysis technologies have provided an opportunity to link variable treatment responses to specific underlying genotypes, highlighting the enormous genomic heterogeneity in human cancer and its role in the response to therapy, and revealing the need to reconsider the scale of cell line-based studies to assess the activity of candidate anticancer agents.

  • Consequently, much larger panels of cancer cell lines are beginning to be exploited for the purpose of identifying genomic determinants of drug sensitivity, and several studies have validated the usefulness of this approach to reveal clinically informative biomarkers.

  • This development, together with additional technological developments involving various three-dimensional culture systems and more sophisticated xenograft models, has recently reinvigoratedthe application of cancer cell lines to the analysis of drug efficacy in cancer.

  • Although throughput, as well as the physiological relevance of some of these approaches, remains a limitation of these systems, there seems to be little doubt that tumour-derived cell lines will continue to have a vital role in the preclinical assessment of new candidate anticancer agents.

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Figure 1: Three-dimensional cell culture assays.

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Acknowledgements

We apologise to the authors of many relevant publications that we were unable to cite owing to space limitations.

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Correspondence to Jeff Settleman.

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The authors declare no competing financial interests.

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DATABASES

National Cancer Institute Drug Dictionary 

bevacizumab

cetuximab

dasatinib

erlotinib

gefitinib

gemcitabine

imatinib

lapatinib

nilotinib

panitumumab

sorafenib

sunitinib

trastuzumab

FURTHER INFORMATION

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Cancer Cell Line Project

Developmental Therapeutics Program

Glossary

Oncogene addiction

The hypothesis that tumours arising as a result of a particular oncogenic lesion remain dependent on the continued expression of that oncogene.

Oncogenic shock

A mechanism to explain oncogene addiction, in which acute inactivation of an oncoprotein is associated with differential attenuation rates of pro-survival and pro-apoptotic signals emanating from the oncoprotein, such that apoptotic signals become predominant and kill the cancer cell.

Synthetic lethality

Two genes are synthetic lethal if mutation of either one of the two genes is compatible with viability but mutation of both genes results in cell lethality.

Lineage addiction

The strict requirement for certain lineage-specific genes in tumorigenesis (for example, melanocyte-specific genes in melanomas).

Non-oncogene addiction

Cancer cells might harbour potential therapeutic targets that do not correspond to oncogenes but constitute proteins to which the cancer cell is similarly addicted.

Clustered heat map

A data matrix display in which the values of a variable in a two-dimensional map are represented as colours.

COMPARE algorithm

A computer program, which compares the pattern of drug sensitivity, as revealed by the NCI60 analysis, to a test compound with the sensitivity profile of all drugs previously tested against the NCI60 panel. Drugs with similar cell line sensitivity profiles tend to have a similar mode of action.

Cancer Cell Line Project

A project within the Cancer Genome Project, it is focused on genetic characterization of all human cancer cell lines currently used in laboratories. The analysis includes loss of heterozygosity and copy number analysis, detection of microsatellite instability and deep resequencing of all known cancer genes. Currently, the project involves 784 cell lines and 51 of the most common cancer genes.

Orthotopic model

Tumours generated by the introduction of human tumour fragments or cells into the same anatomical sites in an animal as those from which the tumour arose in humans.

Autochthonous model

An endogenous or in situ tumour that evolves from normal cells in an animal (for example, chemically induced tumours). This is in contrast to tumour models in which exogenous tumour cells are implanted into an animal (xenografts).

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