Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

Clinical Applications of Pharmacogenomics in Cancer Therapy
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select an alternative analgesic for patients who are PMs of CYP2D6 or monitor for
insufficient pain control. 21 Clinicians can use PGx biomarkers to predict the severity of
toxicity based on the patient’s genetic profile, enabling a more individualized therapy,
which is thought to have higher selection for cancer cells than non-cancer cells. The
PGx-based monitoring can also significantly improve the prognosis of cancer patients
and potentially decrease the toxic effects of anticancer drugs on normal cells. 4,8,21,22
By identifying the biomarkers associated with severe and potentially lifethreatening
drug toxicity for cancer patients, PGx may hold the potential to minimize
drug toxicity while maximizing drug response and improving patients’ outcomes.
These biomarkers can be divided into three major categories: 20–23
1. Drug-metabolizing enzyme: DME plays an important role in PGx by inactivating
many chemotherapeutic drugs and activating some chemotherapeutic
prodrugs. The genetic polymorphisms of these drug metabolism-related
potential biomarkers have important effects on drug efficacy and sensitivity
to toxicity. Table 6.2 lists some key biomarkers associated with potentially
severe cancer treatment toxicities, many of which are cited in FDAapproved
drug labels. 4,9–19 Table 6.3 outlines the clinical implications of
genetic polymorphisms in chemotherapeutic agent–metabolizing enzymes,
such as CYP450, glutathione S-transferase (GST), uridine diphosphate–
glucuronosyltransferase (UGT), TPMT, and dihydropyrimidine dehydrogenase
(DPD). 4,24–38
2. Drug transporters: Genetic polymorphisms of drug transporters are key
contributors to multidrug resistance (MDR) to cancer treatments, which
may lead to decreased efficacy and unpredictable toxicity associated with
the drug therapy. The key players of MDR are a group of membrane transporters
known as ATP-binding cassette (ABC), and organic cation transporter
(OCT), both of which play a critical role in drug efflux, especially for
chemotherapeutic agents. 4,39
3. Drug targets and associated signal transduction: Biomarkers for the selective
therapy are usually associated with targeted therapeutic agents directed
at tumor cells with particular protein characteristics that significantly differ
from their normal cell counterparts. By identifying specific PGx biomarkers
present in tumors, physicians can select and tailor a patient’s treatment
based on his or her genetic profile. Thus, targeted therapy guided by PGx
biomarkers has the potential to be more selective for cancer cells than
for normal cells, which can significantly improve the prognosis of cancer
patients and potentially decrease the toxic effects of anticancer drugs on
normal cells. Examples of these indicators include epidermal growth factor
receptor (EGFR), K-RAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene
homolog), human epidermal growth factor receptor-2 (HER2), and
stem cell growth factor receptor (c-Kit). 7,22 Table 6.4 lists the PGx biomarkers
associated with cancer treatments cited in FDA-approved drug labels.
These common PGx biomarkers play an important role in cancer treatment
by identifying responders from nonresponders to medications, avoiding
ADRs, and optimizing drug dose. 8,40–45