Advances in high-throughput genomic-scanning have expanded the repertory of genetic GDC-0980 (RG7422) 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. for the development of an arsenal of anti-ErbB therapeutics ranging from small GDC-0980 (RG7422) 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 GDC-0980 (RG7422) 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 GDC-0980 (RG7422) based on recent advances in deep sequencing technologies and to address challenging issues for a better understanding of the functional impact of single 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. placebo+trastuzumab+docetaxel (control arm) showed a survival improvement in the pertuzumab arm and also demonstrated that ErbB2 marker is suited for patient selection for the pertuzumab-based regimen in ErbB2-positive metastatic breast cancer or locally recurrent unresectable tumor (Baselga et al. 2014 Fleeman et al. 2015 Table 1 Representative FDA approved and experimental anti-ErbB therapeutic agents. Despite of these successes there remain major obstacles in achieving sustained response or cure with anti-ErbB inhibitors. The first obstacle refers to or intrinsic resistance seen Rabbit Polyclonal to ADCY8. in patients expressing the ErbB targets yet failing to respond to anti-ErbB. This form of resistance is estimated to occur in up to ~20 and ~70% of ErbB2-positive patients with early and metastatic breast cancer treated with trastuzumab monotherapy respectively (Harris et al. 2007 Wolff et al. 2007 The second type of resistance is the acquired form attributed to drug selection and can be seen in over 50% of patients who initially respond to anti-ErbB therapeutics but later become refractory to these drugs (Harris et al. 2007 Wolff et al. 2007 Studies in preclinical models revealed intrinsic and acquired resistance to anti-ErbB therapeutics to involve multifactorial mechanisms both tumor- and host-related (Rexer and Arteaga 2012 Briefly mechanisms of primary drug resistance include emergence of pre-existing tumor cell subpopulations with (i) specific mutations in ErbB genes affecting the drug-target interaction; (ii) alternate splicing of ErbB gene leading to truncated isoforms of the receptors not recognized by the inhibitor e.g. trastuzumab resistance in breast cancer has been associated with the expression of a truncated p95-ErbB2 receptor isoform that lacks trastuzumab antibody binding site; (iii) decreased MAb-induced cell-mediated cytotoxicity in ErbB2-positive cells such as due to an alteration in the binding of immune cells to Fc region of the MAb; and (iv) failure of MAb such as trastuzumab to induce ErbB2 receptor shedding internalization and/or degradation by ubiquitination (Rexer and Arteaga 2012 In contrast to intrinsic resistance a broader range of mechanisms induced by drug pressure can mediate acquired resistance. These include secondary mutations that affect drug-ErbB target interaction (the most common are mutations in the TK domain) activation of compensatory signaling pathways able to bypass signaling blockade by the ErbB inhibitors inefficient cellular transport/uptake of the drug enhanced drug inactivation such as by phase II enzymes up-regulation of survival signals and altered drug pharmacokinetics and.