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Page 448 Michaelis et al. Cancer Drug Resist 2019;2:447-56 I http://dx.doi.org/10.20517/cdr.2019.005

Figure 1. Many cancer diseases respond initially well to therapy but cancer cells become eventually resistant to therapy. An improved
understanding of the mechanisms and processes underlying resistance formation is necessary to identify biomarkers that guide the use
of efficient next-line therapies for tumours that have do not respond to the available standard therapies anymore

advanced cancers that require systemic therapy, typically metastatic disease. In such advanced cases, the
[1-8]
impetus typically lies on the prolongation of life and the improvement of quality of life .

The efficacy of systemic anti-cancer therapies is limited by the occurrence of resistance. Resistance can be
“intrinsic” or “upfront”, i.e., cancer cells do not respond to therapy from the outset. Many cancer diseases,
however, initially respond well to therapy, but after a temporary response resistant cancer cells emerge
leading to “acquired” resistance, ultimately resulting in therapy failure and patient death [8-19] . Hence, cancer
diseases that have become resistant to the available treatment options represent an unmet clinical need. New
strategies including new biomarkers that indicate effective follow-up therapies (on an individualised basis)
are needed for such patients for which no established therapy options are available anymore [Figure 1].

INTRINSIC AND ACQUIRED RESISTANCE MECHANISMS MAY DIFFER
There is a conceptional difference between the mechanisms and processes underlying intrinsic and acquired
drug resistance formation. Intrinsic resistance is the consequence of pre-existing, potentially stochastic
changes that render cancer cells insensitive to the standard treatment. In contrast, acquired resistance is
the consequence of selection and adaptation processes in response to therapy, i.e., of directed evolution
induced by the therapy. In line with this, differences have been described between intrinsic and acquired
resistance mechanisms [20-23] . Hence, acquired resistance needs to be studied in the context of the underlying
(co)-evolutionary processes to establish a specific systems level understanding.

PRECLINICAL MODEL SYSTEMS ARE NEEDED TO DELIVER BIOMARKERS FOR THE
EFFECTIVE USE OF “LIQUID BIOPSIES” FOR THERAPY MONITORING
The systematic elucidation of resistance formation depends on the combined use of preclinical model
systems in combination with clinical data and specimens. Preclinical model systems enable in-depth
functional and systems level studies that are difficult or impossible to perform using primary cancer
cells, tissues, and/or organoids. In addition, non-standard treatments can be systematically investigated
in preclinical model systems. This is not possible in a clinical setting, where patients receive standard
therapies that provide the highest probability of treatment success. Hence, biomarkers that: (1) identify
(small) groups of patients that are unlikely to respond to standard therapies; and (2) guide the use of more
promising therapies to such patients need to be derived from preclinical models. Finally, preclinical model
systems enable the direct comparison of different therapies in the same system. Such comparisons are not
possible in the clinics, where every patient can only be treated once.

So-called “liquid biopsies” including circulating tumour DNA and circulating tumour cells enable the
[24]
monitoring of cancer evolution and therapy response in ever greater detail . The clinical implementation