Pharmacogenomics of intrinsic and acquired pharmacoresistance in colorectal cancer: Toward targeted personalized therapy

Abstract

Colorectal cancer (CRC) represents one of the most common malignancies and is major cause of cancer-related deaths worldwide. A great improvement in response rate and patient's survival was recently achieved through the introduction of new targeted agents including the anti-EGFR monoclonal antibodies cetuximab and panitumumab, the anti-angiogenic drugs bevacizumab and aflibercept, as well as the multi-kinase inhibitor regorafenib, in combination with standard fluoropyrimidines-based chemotherapeutic regimens. Intrinsic and acquired chemoresistance continue to be a major hindrance toward curative therapy. To overcome the obstacle of the currently unpredictable inter-individual variability in the therapy outcome, concentrated research efforts have been focused on elucidating the contribution of genetic variants predictive of pharmacoresistance in CRC. The occurrence of tumor somatic mutations in the RAS/RAF/MAPK and PI3K/PTEN/AKT pathways remains the main challenge for CRC treatment with the new biological agents. It has been recently proposed to consider a quadruple negative profile for CRC, based on the status of KRAS exon 2, BRAF-p.V600E, PI3KCA-exon 9 and PTEN, as tumor markers of sensitivity to anti-EGFR treatment. However, in the last years, great efforts have been devoted to address germline genetic profiles of pharmacoresistance. Heritable genetic variants in the ABC and SLC transport pathways; in the CYP450, GST, and UGT-mediated phase I and II metabolism; in the folate metabolic pathway; as well as in the EGF and VEGF signaling pathways, have been associated with a distinct tumor sensitivity phenotype in CRC patients treated with fluoropyrimidines combined with either irinotecan, oxaliplatin or targeted biological agents. More recently, computation of clinical-pharmacogenetic algorithms, combining multiple host polymorphisms with clinico-demographic features, appeared to be a more reliable strategy to test a complex phenomenon as tumor response to therapy. The final goal of the pharmacogenomics research in the domain of pharmacoresistance in CRC should be the definition of integrated somatic and germline genetic profiles of both intrinsic and acquired resistance. The aim of the present review is to provide a comprehensive update on the most important findings regarding the research of pharmacogenomics markers in the field of CRC treatment that could be integrated in clinical practice in order to accomplish an efficacious personalized treatment.