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Page 450 Michaelis et al. Cancer Drug Resist 2019;2:447-56 I http://dx.doi.org/10.20517/cdr.2019.005

Figure 2. Members of the ATP-binding cassette (ABC) transporter family, including ABCB1 and ABCC1 as prominent members, belong to
the most important mediators of drug resistance in cancer. Various members of the ABC transporter family function as efflux pumps that
remove (often a wide range of structurally different anti-cancer drugs) from cancer cells and interfere with the achievement of effective
intracellular drug concentrations

[52]
2 proteins . Furthermore, erlotinib-resistant colonies derived from non-small cell lung cancer cell lines
[53]
reflected clinically observed resistance mechanisms .
Drug-adapted cancer cell lines have also been shown to reflect clinical resistance formation to other kinase
inhibitors that target specific oncogenic driver events. Inhibitors that specifically target constitutively active
oncogenic V600E-mutant BRAF, have improved the therapy of melanoma patients whose tumours consist
of cells that harbour V600E BRAF mutations. Unfortunately, responses are short-lived, and resistance
[54]
formation is inevitable . Key acquired resistance mechanisms to V600E-specific BRAF inhibitors
including NRAS mutation, BRAF amplification, dimerization of aberrantly spliced V600E-mutant BRAF,
and PDGFRB upregulation were all identified in drug-adapted cancer cell lines [55-57] . Moreover, clinically 5
relevant resistance mechanisms were represented in EGFR, HER2, and ALK inhibitor-adapted cancer cell
lines [58,59] .

Drug-adapted cancer cell lines also reflect clinical resistance formation against various other “targeted”
anti-cancer drugs that interfere with features that are exclusively or predominantly found in cancer
cells, as demonstrated by the following examples. Prostate cancer cell lines adapted to the antiandrogen
enzalutamide enabled the identification of F876L mutations in the androgen receptor as a clinically relevant
resistance mechanism [60,61] . MDM2 inhibitors are under development as a novel class of anti-cancer drugs
for the treatment of TP53 wild-type cancer cells from different cancer entities. TP53 encodes p53, a major
tumour suppressor protein. MDM2 is a p53 target gene that encodes for MDM2, a major endogenous
inhibitor of p53. MDM2 physically interacts with p53 and mediates its ubiquitination and proteasomal
degradation. MDM2 inhibitors activate p53 signalling by interference with the MDM2/p53 interaction [62-64] .
Adaptation of TP53 wild-type cancer cell lines has been associated with the formation of loss-of-function
TP53 mutations in many model systems [65-70] . In agreement, MDM2 inhibitor treatment of liposarcoma
[71]
patients was associated with the emergence of TP53 mutations .
Drug-adapted cancer cell lines are also used to elucidate resistance mechanisms to cytotoxic anti-cancer
agents. A subfraction of cells that critically depend on notch- and hedgehog signalling have been shown to
[72]
be critically involved in resistance formation to doxorubicin in castration-resistant prostate cancer cells .
A number of recent studies investigated resistance formation in acute myeloid leukaemia cells using drug-
adapted cell lines and identified GLI1, EZH2, and SAMHD1 as clinically relevant resistance mechanisms to
cytarabine-based therapies [73-75] . In addition, increased glucocorticoid sensitivity was detected in cytarabine-
[76]
adapted acute myeloid leukaemia cell lines and patient samples . The use of drug-adapted cell lines has