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Cancer Drug Resist 2018;1:266-302 I http://dx.doi.org/10.20517/cdr.2018.18 Page 267

geneity found in many types of cancer, it is assumed that resistant tumor cells are already present in many
patients at the time of therapeutic intervention; on the other hand, the administered drugs result in a selec-
tion of tumor cell clones that have developed de novo mutations favorable for tumor cell survival. Moni-
toring of genetic alterations in the course of systemic cancer disease at close intervals could thus help in
recognizing the development of resistance at an early stage and in selecting the most appropriate therapy
for each patient. For this, we established a liquid biopsy platform and single cell technologies to follow the
genetic evolution of systemic cancer.

3. The resistant cancer cell line collection: drug-adapted cancer cell lines as preclinical

models of acquired drug resistance

1
1
Martin Michaelis , Mark N. Wass , Cinatl J. Jr 2
1 Industrial Biotechnology Centre and School of Biosciences, University of Kent, Canterbury, UK
2 Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Frankfurt am Main, Germany

Acquired resistance formation is a major reason for the failure of anti-cancer therapies. Pre-clinical model
systems are needed to complement data derived from clinical specimens such as liquid biopsies to establish
the understanding of the resistance formation process required to improve therapies. Cancer cell lines en-
able the generation of the large number of model systems needed to cover the complexity of the resistance
mechanisms. Major resistance mechanisms have been discovered in drug-adapted cell lines, e.g., high
levels of the ATP-binding cassette (ABC) transporters ABCB1 (also P-glycoprotein, MDR1) and ABCC1
(also MRP1). Moreover, various groups have used drug-adapted cancer cell lines to identify and elucidate
clinically relevant acquired resistance mechanisms to targeted and cytotoxic anti-cancer drugs. We have
established the resistant cancer cell line (RCCL) collection by adapting initially chemosensitive cancer cell
lines to clinical concentrations of targeted and cytotoxic anti-cancer drugs. It currently contains 1,300
cancer cell lines based on 125 parental cell lines from 15 cancer entities and reflects acquired resistance to
67 drugs (https://research.kent.ac.uk/ibc/the-resistant-cancer-cell-line-rccl-collection). Using RCCL collec-
tion cell lines, we and others identified (clinically relevant) drug resistance mechanisms and have gained
insights into the action of anti-cancer drugs. For example, we have shown that acquisition of resistance to
MDM2 inhibitors is associated with TP53 mutations, which has been clinically confirmed. Furthermore,
we have identified high SAMHD1 expression as a resistance mechanism in cytarabine-adapted acute my-
eloid leukaemia cell lines and, in turn, shown that SAMHD1 is a biomarker for cytarabine response in
the clinic and a novel therapeutic target in acute myeloid leukaemia. In conclusion, drug-adapted cancer
cell lines reflect clinically relevant acquired drug resistance mechanisms. The RCCL collection is a readily
available tool containing a substantial number of preclinical models of acquired drug resistance in cancer.

4. Prospects and limitations of patient-derived xenografts in translational cancer research

Iduna Fichtner 1,2

1 Max Delbrück Center, Berlin, Germany
2 Experimental Pharmacology and Oncology GmbH, Berlin, Germany

The molecular analysis of tumours by highly sophisticated gene expression and sequencing methods allows
the comprehensive identification of drugable targets and the increasing chance for personalized treatments.
Clinically established examples are the use of Imatinib for BCR-ABL positive leukemias and Vemurafenib