Pharmacogenomics of EGFR-targeted therapies in non-small cell lung cancer: EGFR and beyond.

Christopher Delaney,Samuel Frank,R Stephanie Huang

doi:10.1186/s40880-015-0007-9

Christopher Delaney, Samuel Frank + Show 1 more

Open Access

https://doi.org/10.1186/s40880-015-0007-9

Copy DOI

Abstract

Commonly observed aberrations in epidermal growth factor receptor (EGFR) signaling have led to the development of EGFR-targeted therapies for various cancers, including non–small cell lung cancer (NSCLC). EGFR mutations and overexpression have further been shown to modulate sensitivity to these EGFR-targeted therapies in NSCLC and several other types of cancers. However, it is clear that mutations and/or genetic variations in EGFR alone cannot explain all of the variability in the responses of patients with NSCLC to EGFR-targeted therapies. For instance, in addition to EGFR genotype, genetic variations in other members of the signaling pathway downstream of EGFR or variations in parallel receptor tyrosine kinase (RTK) pathways are now recognized to have a significant impact on the efficacy of certain EGFR-targeted therapies. In this review, we highlight the mutations and genetic variations in such genes downstream of EGFR and in parallel RTK pathways. Specifically, the directional effects of these pharmacogenetic factors are discussed with a focus on two commonly prescribed EGFR inhibitors: cetuximab and erlotinib. The results of this comprehensive review can be used to optimize the treatment of NSCLC with EGFR inhibitors. Furthermore, they may provide the rationale for the design of subsequent combination therapies that involve the inhibition of EGFR.

Highlights

Non–small cell lung cancer (NSCLC) accounts for nearly 80% of all lung cancers and is the leading cause of cancer-related deaths worldwide [1,2]
While no specific evidence links genetic variations in NFκB or NFKBIA with drug efficacy on NSCLC, patients with colorectal cancer whose tumors are negative for NF-κB expression have a positive predictive response to cetuximab and a longer overall survival compared with patients whose tumors are positive for NF-κB expression; the results were similar after erlotinib treatment in patients with NSCLC (Table 1) [1,88]
We need to gain a better understanding of why these patients with hyperactive epidermal growth factor receptor (EGFR) signaling have such variable responses to EGFRtargeted therapies by designing studies to explore variation in other non-EGFR genes

Summary

Introduction

Non–small cell lung cancer (NSCLC) accounts for nearly 80% of all lung cancers and is the leading cause of cancer-related deaths worldwide [1,2]. Recent and compelling evidence suggests that genetic variations in other members of the signaling pathway downstream of EGFR, and in the non-EGFR receptor tyrosine kinase (RTK) pathways, can influence responses to cetuximab and erlotinib.

Results

Conclusion