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

Viktor Hlaváč,Pavel Souček,Petr Holý

doi:10.3390/jpm10030108

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.

Highlights

A similar situation exists in the Catalogue of Somatic Mutations in Cancer (COSMIC) database (v91), a massive database that consists of more than 6 million coding mutations measured in 1.4 million tumor samples, manually curated from over 26 thousand publications [83]
Promising examples of clinical applications of pharmacogenomics may be seen in the area of targeted therapy of selected cancers with TKIs and the list is envisaged to expand soon
Research of ATP-binding cassette (ABC) and cytochrome P450 (CYP) in pharmacology and oncology was directed at their expression and germline genetic variation

Summary

Introduction

Recent studies on Exome Aggregation Consortium (ExAC) and the 1000 Genomes Project corroborate the importance of rare genetic variants in the pharmacogenetic prediction of drug response [7,8]. This article will focus solely on the genomic variation in ABC transporters and CYPs and their possible roles in tumor therapy responses and will outline the most recent findings, summarizing the perspectives of their potential use in personalized therapies on germline, somatic and copy number levels. Germline variants in many of the VIPs of CYP and ABC superfamilies as well as in other genes (ABCB4, ABCC1-C4, CYP1A1, and CYP1B1) are associated with drug response in cancer. 5-FU, anthracycline, cyclophosphamide tegafur cyclophosphamide, doxorubicin, imatinib cyclophosphamide, doxorubicin, tamoxifen tamoxifen, gefitinib cisplatin, cyclophosphamide paclitaxel imatinib anastrozole, letrozole, tamoxifen efficacy dosage efficacy

Somatic Variants in ABCs and CYPs in Solid Tumors

Copy Number Variants in ABCs and CYPs

Long Noncoding RNA Regulation

Findings

Conclusions