Pharmacogenomics to Predict Tumor Therapy Response: A Focus on ATP-Binding Cassette Transporters and Cytochromes P450

Abstract

Pharmacogenomics is an evolving tool of precision medicine. Recently, due to the introduction of next-generation sequencing and projects generating "Big Data", a plethora of new genetic variants in pharmacogenes have been discovered. Cancer resistance is a major complication often preventing successful anticancer treatments. Pharmacogenomics of both somatic mutations in tumor cells and germline variants may help optimize targeted treatments and improve the response to conventional oncological therapy. In addition, integrative approaches combining copy number variations and long noncoding RNA profiling with germline and somatic variations seem to be a promising approach as well. In pharmacology, expression and enzyme activity are traditionally the more studied aspects of ATP-binding cassette transporters and cytochromes P450. In this review, we briefly introduce the field of pharmacogenomics and the advancements driven by next-generation sequencing and outline the possible roles of genetic variation in the two large pharmacogene superfamilies. Although the evidence needs further substantiation, somatic and copy number variants as well as rare variants and common polymorphisms in these genes could all affect response to cancer therapy. Regulation by long noncoding RNAs has also been shown to play a role. However, in all these areas, more comprehensive studies on larger sets of patients are needed.

Keywords: ATP-binding cassette transporters; cancer therapy; cytochromes P450; omics; personalized medicine; pharmacogenomics; response.

Figure 1

Major functional aspects of ATP-binding cassette (ABC)/cytochrome P450 (CYP) in drug responses with the presumed role of their genetic variability.

Figure 2

Top 30 mutated ATP-binding cassette transporters in top 200 mutated cases in The Cancer Genome Atlas (TCGA) across the four most common cancers types. The results shown here are in whole based upon data generated by the TCGA Research Network: [81].

Figure 3

Top 30 mutated cytochromes P450 in top 200 mutated cases in TCGA across the four most common cancers types. The results shown here are in whole based upon data generated by the TCGA Research Network: [81].