Nuclear receptors and drug metabolism for the personalization of cancer therapy

ABSTRACT

Introduction: A remarkable inter-individual variability in the occurrence of severe side effects represents an ongoing challenge in cancer treatment. Significant research efforts have focused on elucidating the contribution of the host genetic variability, but only a few markers have been identified for use in clinical practice. Several studies demonstrated that PXR and CAR activation can affect the expression of genes involved in absorption, distribution, metabolism and excretion (ADME) of antineoplastic drugs. The study of the host genetic background of Pregnane X Receptor (PXR; NR1I2) and Constitutive Androstane Receptor (CAR; NR1I3 and NR1I4), represents a new and attractive strategy to discern variability in ADME of antineoplastic drugs.

Areas covered: An update of the most important findings about investigational CAR and PXR pharmacogenetic markers of anti-cancer drugs toxicity is provided.

Expert opinion: A differential activation of PXR and CAR can affect the pharmacokinetics and pharmacodynamics of antineoplastic drugs. Pharmacogenetics studies published up to date provide encouraging even if exploratory results. Future large and prospective studies will clarify the clinical value of PXR and CAR genetic markers in treatment personalization.

KEYWORDS:

• Cancer
• CAR
• nuclear receptors
• PXR
• toxicity

Article highlights

• Nuclear receptors are hypothesized to provide a crucial contribute to the integration of the environmental influences on the drug effect phenotype by regulating DM enzymes and ABC/SLC transporters expression. PXR and CAR are the NRs most extensively studied in this field.

• PXR/CAR expression in cancer cells was demonstrated to be predictive of the chemotherapy efficacy in colorectal, prostate and gynecological tumor, although most of the data derived from in vitro studies.

• The drugs that appeared to be affected by PXR and CAR expression are substrates of CYPs (CYP3A4, CYP3A5, CYP2B6), UGT1As (UGT1A1, UGT1A7, UGT1A9-10) and transporters (ABCB1, ABCC1-3, ABCG2, SLCO1B1) as for example irinotecan, platinum derivates, cyclophosphamide, taxanes and some new targeted agents (i.e. sorafenib and tyrosine kinase inhibitors).

• The study of PXR and CAR polymorphic variants in the clinical setting, for association with drug toxicity and pharmacokinetics, provided up to date only preliminary results on a limited set of drugs (doxorubicin, sunitinb, taxanes).

• CAR rs2307424, rs2307418, and rs4073054; and PXR rs3814055 and rs2276707 were the most promising pharmacogenetic markers and were also related to the treatment efficacy of sunitinib or pazopanib in advanced renal cell cancer patients.

• Although the importance of PXR and CAR activation in modulating anti-cancer treatment effectiveness is well established, prospective studies are needed to understand the clinical value of PXR and CAR genetic polymorphisms in the personalization of cancer treatment.

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Declaration of interest

The authors were supported by Associazione Italiana per la Ricerca sul Cancro (AIRC); (Special Program Molecular Clinical Oncology, 5x1000, [No. 12214]). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.