The Resistant Cancer Cell Line (RCCL) collection


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Martin Michaelis1, Mark Wass1, Jindrich Cinatl2
1University of Kent, Canterbury, UK,2Goethe-University, Frankfurt am Main, Germany

Abstract

Background

The formation of acquired resistance is a major reason for the failure of anti-cancer therapies. Cancer cell lines enable the generation of the large number of model systems needed to cover the complexity of the resistance formation process. Major resistance mechanisms have been discovered in drug-adapted cell lines, e.g. the ATP-binding cassette (ABC) transporters ABCB1 (also known as P-glycoprotein or MDR1) and ABCC1 (also known as MRP1). Moreover, drug-adapted cancer cell lines have been used by various research groups to identify and investigate clinically relevant acquired resistance mechanisms to targeted and cytotoxic anti-cancer drugs.

Method

We have established the Resistant Cancer Cell Line (RCCL) collection by adapting initially chemosensitive cancer cell lines to therapeutic concentrations of anti-cancer drugs.

Results

The RCCL collection contains 1300 cancer cell lines based on 125 parental cell lines from 15 cancer entities. It reflects acquired resistance to 67 targeted and cytotoxic anti-cancer drugs. Using RCCL collection cell lines, we have identified (clinically relevant) drug resistance mechanisms. For example, we have shown that acquisition of resistance to MDM2 inhibitors is associated with de novo p53 mutations, which has recently been clinically confirmed. Furthermore, we have demonstrated that high SAMHD1 expression is a resistance mechanism in cytarabine-adapted acute myeloid leukaemia cell lines. Based on this discovery, we have identified SAMHD1 as a biomarker for cytarabine response in the clinic and a novel therapeutic target in acute myeloid leukaemia.

Conclusion

Our data and those of others confirm that drug-adapted cancer cell lines reflect clinically relevant acquired drug resistance mechanisms. In addition, drug-adapted cancer cell lines can be used to elucidate the mechanism of action of anti-cancer drugs. The RCCL collection is a readily available tool for the studying of drug-induced cancer cell resistance mechanisms, the investigation of anti-cancer agents, and the examination of drug-induced clonal evolution processes.

Background

The heterogeneity and individuality of cancer diseases is tremendously high. Recent genomic investigations revealed a tremendous genetic complexity in the cells from solid cancer diseases. Cancer cell (sub)populations may differ substantially between primary tumours and metastases as well as within primary tumours. This heterogeneity is a consequence of cancer clonal evolution processes. Among other models, comprehensive cancer cell line collections will be required to address this wide complexity. Resistance acquisition to anti-cancer therapies represents a major obstacle to the development of effective anti-cancer therapies. Major cancer cell drug resistance mechanisms have been discovered in drug-adapted cancer cell lines including the ABC transporters ABCB1 (also known as P-glycoprotein or MDR1) and ABCC1 (also known as MRP1) and clinically relevant resistance mechanisms to so-called "targeted therapeutics" (e.g. EGFR tyrosine kinase inhibitors, oncogenic BRAF inhibitors, anti-androgens).

Method

Initially chemosensitive cancer cell lines are adapted to growth in the presence of clinical concentrations of anti-cancer drugs.

Results

The Resistant Cancer Cell Line (RCCL) collection consists of > 1000 cell lines from 15 different cancer entities with acquired resistance to a broad range of cytotoxic and targeted anti-cancer drugs (www.kent.ac.uk/stms/cmp/RCCL/RCCLabout.html).

Conclusion

The RCCL collection is a readily available tool for the studying of drug-induced cancer cell resistance mechanisms, the investigation of anti-cancer agents, and the examination of drug-induced clonal evolution processes.