Cancer Pharmacogenetics: The Move from Pharmacokinetics to Pharmacodynamics

Drug response is a complex process determined by both genetic and non-genetic factors. Factors that control drug response can be divided into those that affect the systemic distribution and the concentration of drug at its target (pharmacokinetics) and those associated with drug targets and cellular downstream effectors (pharmacodynamics). Most pharmacogenetic studies to date have focused on the influence of genetic variation in determinants of drug distribution. Consistent associations between host polymorphisms in drug metabolising enzymes, including UGT1A1, TPMT and DPD and patient toxicity or response to chemotherapies have been demonstrated. Less is known about the cellular events following exposure to anticancer agents that lead to DNA repair or cell death, making them more difficult to study. Genetic variation in these downstream effectors is a potential source of interindividual differences in tumoral response. Exciting associations between tumor sensitivity to tyrosine kinase inhibitors and somatic mutations in their drug targets (for example epidermal growth factor receptor (EGFR)) have recently been demonstrated. These findings take us closer to personalized therapy. This paper reviews the latest advances in cancer pharmacogenetics with an emphasis on genetic variation in drug targets and mediators of cellular events that occur following drug-target interactions.