Pharmacogenomics of Targeted Agents for Personalization of Colorectal Cancer Treatment

Abstract

The use of targeted agents in the treatment of metastatic colorectal cancer (CRC) has improved patient outcomes. Anti-epidermal growth factor receptor (anti-EGFR) agents (cetuximab and panitumumab) and antiangiogenic molecules (bevacizumab, regorafeninb, ramucirumab, and aflibercept) have been successfully integrated into clinical practice. Other drugs have been designed to target additional deregulated pathways in CRC, such as MAPK (mitogen-activated protein kinase)/PI3K-AKT (phosphatidylinositol-3-kinase-AKT serine/threonine kinase)/mTOR (mammalian target of rapamycin), HER-2 and 3 ( human epidermal growth factor receptor-2 and -3), and BRAF. A major issue with targeted treatment is early identification of patients with primary or secondary drug resistance. Pharmacogenomic research has demonstrated its value in this field, highlighting some tumor mutations that could discriminate responders from non-responders. The tumor genetic profile of the RAS/RAF pathway is needed before treatment with anti-EGFR agents; mutations in EGFR pathway genes have also been explored in relation to antiangiogenic molecules although further data are required prior to their integration into clinical practice. The introduction of immunotherapy has paved the way for a new generation of predictive markers, including genome-wide assessment of the tumor landscape. Furthermore, the development of next generation sequencing technology and non-invasive approaches to analyze circulating tumor DNA will make real-time monitoring of the tumor pharmacogenomic markers possible in the clinical routine, rendering precision medicine available to every patient.

Novel Somatic Genetic Variants as Predictors of Resistance to EGFR-Targeted Therapies in Metastatic Colorectal Cancer Patients

“…This result is not striking as resistant mCRC phenotypes tend to be more heterogeneous than sensitive phenotypes [ 58 ]. Our results are in keeping with most papers to date describing mutations of non-response to anti-EGFR antibodies [ 59 , 60 , 61 ]. Only three of the eight somatic variants identified had been previously described [ 26 ], strengthening the extreme phenotype approach as a useful strategy to identify rare alterations.…”

Nigericin Exerts Anticancer Effects on Human Colorectal Cancer Cells by Inhibiting Wnt/β-catenin Signaling Pathway

“…There is a constant demand for new therapies. Thus, additional new therapeutic agents or approaches that target colorectal cancer are urgently needed (3).…”

RNA sequencing profiles and diagnostic signatures linked with response to ramucirumab in gastric cancer

“…It has been also approved for hepatocellular carcinoma (Zhu et al 2019), non-small cell lung cancer (Garon et al 2014) and colorectal cancer (Tabernero et al 2015). However, to our knowledge so far there is no accepted biomarkers of ramucirumab efficiency in cancers (Vlachostergios et al 2018;Bignucolo et al 2017). We were also unable to find in public domain any clinically annotated high throughput gene expression profiles linked with the patient responses on treatment with ramucirumab.…”