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Kaehler et al. Cancer Drug Resist 2019;2:18-30 I http://dx.doi.org/10.20517/cdr.2019.05 Page 19

treatment often is a double-edged sword balancing best treatment outcome and potential life-threatening
adverse drug effects, pharmacogenetic data is relevant to improve individualized therapy. In this context,
variants in biotransforming enzymes, drug transporters and their regulators are of major interest as potential
biomarkers for improvement of treatment regimen. Here, we discuss the impact of pharmacogenetic testing
in treatment with cytostatics and targeted therapies in the context of drug resistance.

CyTOsTaTICs, TaRgeTeD TheRapy aND beyOND
Due to the lack of specific drug targets in various types of cancer and beneficial effects in combination
therapy, cytostatics are still of major relevance for anticancer treatment. Metabolism and biotransformation of
[4]
these compounds underlie various enzymes and transporters, which are well described . Hence, hereditary
variants in biotransforming enzymes are well known to impair metabolism of drugs, e.g., 5-fluorouracil
(5-FU) or 6-mercaptopurine (6-MP). For several cytostatic compounds, pharmacogenetic information
has been integrated into treatment recommendations of the Federal Drug Administration or guidelines
from the Clinical Pharmacogenetics Implementation Consortium (CPIC), e.g., for 5-FU, irinotecan or
[5]
6-MP . However, some pharmacogenetic markers still have not been translated into clinical practice.

Within the last 15 years, the number of targeted therapies using small molecules and antibodies drastically
expanded with good clinical outcome and increased patient survival. One of the first compounds used was
[6]
trastuzumab, a HER2/neu-antibody for the use in HER2+ breast cancer and the tyrosine kinase inhibitor
[7]
imatinib, which targets the BCR/ABL1-kinase in chronic myeloid leukemia . In contrast to classical
chemotherapeutics, these substances rely on the presence or overexpression of drugable targets on/in the
tumor cells. Therefore, expression of the respective target protein in the cancer cell is mandatory and genetic
testing of cancer patients is compulsory, e.g., for HER2/neu overexpression for the use of trastuzumab,
HER1 for the use of cetuximab or panitumumab or BCR/ABL1/c-kit for the use of imatinib. All of these
compounds are dependent on binding to their target protein, which can be impaired by mutation or
amplification and by this trigger chemoresistance. While this is a concern in treatment with antibodies
and small molecules, drug level of the latter can also be impaired by several other mechanisms. Moreover,
intracellular level can be reduced by ATP-binding cassette (ABC) transporters, which facilitate drug efflux
or diminished expression or activity of drug importers. Some small molecules are substrates for the CYP450
enzymes, by which the drug plasma level could be impaired. These mechanisms leading to impaired drug
level and transport are described below.

heReDITaRy vaRIaNTs IN bIOTRaNsfORmINg eNzymes
Purine analogues, TPMT and NUDT15
The association of thiopurine S-methyltransferase (TPMT) and 6-MP is one of the best documented
pharmacogenetic interactions. This purine analogue, as well as azathioprine or thioguanine, are of major
relevance in therapy of acute lymphoblastic leukemia (ALL) or non-malignant diseases, e.g., inflammatory
bowel disease [8-10] . Its anti-inflammatory and anticancer mechanism is based on the generation of active,
cytotoxic 6-thioguanosines having major negative impact on leucocyte proliferation. TPMT however
prevents the organism from the formation of large amounts of these toxic intermediates through methylation
and conversion to inactive methylmercaptopurine. Therefore, patients with TPMT deficiency suffer from
a high risk of cytotoxicity due to accumulation of thioguanine nucleotides (6-TGN). Complete absence of
[11]
TPMT activity may lead to myelosuppression and pancytopenia [Table 1] .
The frequency of 6-TGN-related hematologic adverse drug events depend on the TPMT genotype, while
intestinal side effects seem to be genotype-independent . Nevertheless, pharmacogenetics testing and
[12]
[13]
subsequent adjusting the purine analogue dose is highly recommended .