人表皮生长因子受体 3 (ERBB3) 是 ERBB 受体酪氨酸激酶 (RTK) 的成员，在许多恶性肿瘤中表达。与其他 ERBB 受体一样，ERBB3 与调节正常细胞增殖、凋亡、分化和存活相关，并且因其参与癌症治疗而受到越来越多的研究关注。 ERBB3 表达或共表达水平已被研究作为癌症预后和药物敏感性的预测因素。此外，ERBB3 表达升高与癌症治疗失败之间的关联进一步确立了 ERBB3 靶向治疗作为一种重要的治疗方法。这篇综述深入探讨了 ERBB3 驱动的对 ERBB2 和 EGFR 靶向治疗以及其他信号转导抑制剂、内分泌治疗、化疗和放疗耐药的分子机制。利用临床前和临床证据，我们综合并阐明了异常 ERBB3 活性的各个方面（例如代偿性激活、信号串扰相互作用、内吞途径失调、突变、配体独立激活、内在激酶活性和同二聚化）如何导致产生耐药性和/或治疗失败。几种针对 ERBB3 的单克隆抗体、双特异性抗体和新兴的抗体-药物偶联物在提高治疗效果和克服耐药性方面表现出令人鼓舞的临床结果，特别是与其他抗癌方法结合使用时。需要更多的研究工作来确定适合 ERBB3 靶向疗法的合适生物标志物。版权所有 © 2024 作者。由 Elsevier B.V. 出版。保留所有权利。

Human epidermal growth factor receptor-3 (ERBB3) is a member of the ERBB receptor tyrosine kinases (RTKs) and is expressed in many malignancies. Along with other ERBB receptors, ERBB3 is associated with regulating normal cell proliferation, apoptosis, differentiation, and survival, and has received increased research attention for its involvement in cancer therapies. ERBB3 expression or co-expression levels have been investigated as predictive factors for cancer prognosis and drug sensitivity. Additionally, the association between the elevated expression of ERBB3 and treatment failure in cancer therapy further established ERBB3-targeting therapy as a crucial therapeutic approach. This review delves into the molecular mechanisms of ERBB3-driven resistance to targeted therapeutics against ERBB2 and EGFR and other signal transduction inhibitors, endocrine therapy, chemotherapy, and radiotherapy. Using preclinical and clinical evidence, we synthesise and explicate how various aspects of aberrant ERBB3 activities-such as compensatory activation, signal crosstalk interactions, dysregulation in the endocytic pathway, mutations, ligand-independent activation, intrinsic kinase activity, and homodimerisation-can lead to resistance development and/or treatment failures. Several ERBB3-directed monoclonal antibodies, bispecific antibodies, and the emerging antibody-drug conjugate demonstrate encouraging clinical outcomes for improving therapeutic efficacy and overcoming resistance, especially when combined with other anti-cancer approaches. More research efforts are needed to identify appropriate biomarkers tailored for ERBB3-targeted therapies.Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.