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Review
. 2015 Feb 4:6:17.
doi: 10.3389/fgene.2015.00017. eCollection 2015.

ErbB polymorphisms: insights and implications for response to targeted cancer therapeutics

Affiliations
Review

ErbB polymorphisms: insights and implications for response to targeted cancer therapeutics

Moulay A Alaoui-Jamali et al. Front Genet. .

Abstract

Advances in high-throughput genomic-scanning have expanded the repertory of genetic variations in DNA sequences encoding ErbB tyrosine kinase receptors in humans, including single nucleotide polymorphisms (SNPs), polymorphic repetitive elements, microsatellite variations, small-scale insertions and deletions. The ErbB family members: EGFR, ErbB2, ErbB3, and ErbB4 receptors are established as drivers of many aspects of tumor initiation and progression to metastasis. This knowledge has provided rationales for the development of an arsenal of anti-ErbB therapeutics, ranging from small molecule kinase inhibitors to monoclonal antibodies. Anti-ErbB agents are becoming the cornerstone therapeutics for the management of cancers that overexpress hyperactive variants of ErbB receptors, in particular ErbB2-positive breast cancer and non-small cell lung carcinomas. However, their clinical benefit has been limited to a subset of patients due to a wide heterogeneity in drug response despite the expression of the ErbB targets, attributed to intrinsic (primary) and to acquired (secondary) resistance. Somatic mutations in ErbB tyrosine kinase domains have been extensively investigated in preclinical and clinical setting as determinants for either high sensitivity or resistance to anti-ErbB therapeutics. In contrast, only scant information is available on the impact of SNPs, which are widespread in genes encoding ErbB receptors, on receptor structure and activity, and their predictive values for drug susceptibility. This review aims to briefly update polymorphic variations in genes encoding ErbB receptors based on recent advances in deep sequencing technologies, and to address challenging issues for a better understanding of the functional impact of single versus combined SNPs in ErbB genes to receptor topology, receptor-drug interaction, and drug susceptibility. The potential of exploiting SNPs in the era of stratified targeted therapeutics is discussed.

Keywords: ErbB receptors; SNPs; anti-ErbB therapeutics; cancer; drug response; resistance.

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Figures

Figure 1
Figure 1
Representation of epidermal growth factor receptors family (EGFR/ErbB1, ErbB2, ErbB3, and ErbB4) showing the distribution of the main SNPs mutations in the extracellular domain, transmembrane region, and intracellular domain comprising the tyrosine kinase and autophosphorylation sites. Boxes represent functional domains: I, extracellular domain sub-region I; II, extracellular domain sub-region II; III, extracellular domain sub-region III; IV, extracellular domain sub-region IV. (Prickett et al., ; Yarden and Pines, 2012).
Figure 2
Figure 2
Distribution of the relative percentage of somatic mutations among different cancers types according to the cataloge of somatic mutations in cancer (COSMIC) database in human primary tumors. Each panel shows mutations rates for corresponding ErbB (A. EGFR; B. ErbB2; C. ErbB3; D. ErbbB4) per tumor tissue affected (http://cancer.sanger.ac.uk/cancergenome/projects/cosmic/).

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