Cancer pharmacogenetics: polymorphisms, pathways and beyond

Key Points The field of pharmacogenetics attempts to use genetic information to predict an individual's drug response. It is especially important in cancer chemotherapy given the narrow therapeutic index of these drugs. So far, pharmacogenetic research has largely focused on the effect of single candidate polymorphisms. However, many of the genetic variants that are associated with extreme drug toxicity are rare and explain only a small portion of the variation seen in drug response. Understanding the interactions of genetic variants within a biological or pharmacological pathway will allow for an improved ability to predict drug response. Folate metabolism — a target of antifolate chemotherapeutic agents and thymidylate-synthase inhibitors — is a biological pathway of substantial interest to pharmacogenetic researchers. Pharmacological pathways are being constructed for the systematic evaluation of the genes that regulate variation in the toxicity and efficacy of anticancer agents. Mouse models show promise in identifying key enzymes in pharmacogenetic pathways and will allow study of genetic variation in these pathways. Inherited genetic variations can affect a patient's response to chemotherapeutic agents given for cancer. Pharmacogenetics aims to use knowledge of these variations to 'tailor' therapy for improved response and reduced toxicity. Most research so far has focused on single polymorphisms. A more comprehensive approach to predict treatment response will be to consider genetic variation in entire biological and pharmacological pathways. Of particular relevance to cancer chemotherapy is folate metabolism, which is the target of methotrexate and 5-fluorouracil. Furthermore, efforts have begun to construct pathways of genes that have pharmacological relevance for individual chemotherapeutic agents. Together, these pathway strategies offer a higher likelihood of achieving the promise of genetically guided cancer therapy.