Alaoui-Jamali Moulay A, Morand Grégoire B, da Silva Sabrina Daniela
Departments of Medicine and Oncology, Segal Cancer Centre and Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University Montreal, QC, Canada.
Departments of Medicine and Oncology, Segal Cancer Centre and Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University Montreal, QC, Canada ; Department of Otolaryngology-Head and Neck Surgery, Sir Mortimer B. Davis-Jewish General Hospital, McGill University Montreal, QC, Canada.
Front Genet. 2015 Feb 4;6:17. doi: 10.3389/fgene.2015.00017. eCollection 2015.
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.
高通量基因组扫描技术的进步扩展了人类编码表皮生长因子受体（ErbB）酪氨酸激酶受体的DNA序列中的遗传变异库，包括单核苷酸多态性（SNP）、多态性重复元件、微卫星变异、小规模插入和缺失。ErbB家族成员，即表皮生长因子受体（EGFR）、ErbB2、ErbB3和ErbB4受体，已被确认为肿瘤发生及进展至转移诸多方面的驱动因素。这一认知为开发一系列抗ErbB疗法提供了理论依据，从小分子激酶抑制剂到单克隆抗体。抗ErbB药物正成为治疗过表达ErbB受体高活性变体癌症的基石疗法，尤其是ErbB2阳性乳腺癌和非小细胞肺癌。然而，尽管表达了ErbB靶点，但由于药物反应存在广泛异质性，其临床益处仅限于一部分患者，这归因于内在（原发性）和获得性（继发性）耐药。在临床前和临床环境中，ErbB酪氨酸激酶结构域的体细胞突变已被广泛研究，作为对抗ErbB疗法高敏感性或耐药性的决定因素。相比之下，关于SNP（其在编码ErbB受体的基因中广泛存在）对受体结构和活性的影响及其对药物敏感性的预测价值，仅有极少信息。本综述旨在基于深度测序技术的最新进展，简要更新编码ErbB受体基因的多态性变异，并探讨一些具有挑战性的问题，以便更好地理解ErbB基因中单个或组合SNP对受体拓扑结构、受体-药物相互作用和药物敏感性的功能影响。还讨论了在分层靶向治疗时代利用SNP的潜力。
