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

162 Applying Pharmacogenomics in Therapeutics
G6PD and Rasburicase and Dabrafenib
Rasburicase, a recombinant urate oxidase, has been approved by the US FDA for the
initial management of plasma uric acid in pediatric and adult patients with leukemia,
l ymphoma, and solid tumors who are receiving anticancer therapy and are expected
to have tumor lysis syndrome. Rasburicase is usually well tolerated; however, several
ADRs are of particular concern. The drug is contraindicated in patients with G6PD
deficiency. Due to the contraindication, the US FDA recommends that patients at
higher risk for G6PD deficiency (e.g., patients of African or Mediterranean ancestry)
should be screened prior to starting rasburicase therapy. 64 The enzyme activity is
easily tested from a blood sample of the patient. Genetic testing can be performed to
check for mutations within families.
G6PD deficiency is the most common disease-causing enzymopathy in humans.
It is a metabolic enzyme involved in the pentose phosphate pathway, which is important
in red blood cell metabolism, and is inherited as an X-linked recessive disorder
that affects 400 million people worldwide. The gene encoding G6PD is highly polymorphic,
with more than 300 variants reported. The excess peroxide due to the deficiency
poses a risk for both hemolytic anemia and methemoglobinemia. Hemolysis
occurred in <1% of the patients who received rasburicase with severe hemolytic
reactions presenting within 2–4 days of the start of rasburicase. 65,66
A new drug for metastatic melanoma was approved by the US FDA in 2014.
Dabrafenib is a kinase inhibitor that blocks the activity of the mutated form of the
V600E BRAF protein, which ultimately inhibits tumor growth. Dabrafenib is indicated
as a single agent for the treatment of patients with unresectable or metastatic
melanoma. As dabrafenib contains a sulfonamide moiety, patients with G6PD deficiency
should be monitored closely, as they are at higher risk of hemolytic anemia.
There is currently no recommendation to test patients with G6PD deficiency prior to
starting dabrafenib. 67
Drug Transporter–Related Biomarkers
Genetic polymorphisms of drug transporters are key contributors to 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 ABC and organic cation transporter (OCT), both of which play a
critical role in drug efflux, especially for chemotherapeutic agents.
There are seven families of ABC transporters, among which three ABC efflux
pumps are particularly important for chemoresistance, including ABCB1 (encoding
P-gp), ABCC1, and ABCG2. P-gp is the most studied drug transporter for MDR in
cancer therapy due to it being a major obstacle for efficient and safe chemotherapy.
ABC transporters are ubiquitously expressed in many normal tissues, and they are
also overexpressed in numerous tumor cells. For example, epithelial cells of GI and
biliary tract, and normal hematopoietic stem cells express ABCB1 and ABCG2.
ABCB1 and ABCC1 expression is shown in GIST, while ABCB1, ABCG2, and
OCT1 are found in mononuclear cells in CML patients. Interestingly, it has been
proven that one of the revolutionary CML treatment agents, imatinib, is an inhibitor