Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, USA; Department of Pathology, Henri Mondor University Hospital, Assistance Publique - Hôpitaux de Paris, Créteil, France; INSERM U955 Team 18, Université Paris Est Créteil - Faculté de Médecine, Créteil, France.
Institut National de la Santé et de la Recherche Médicale U938, Centre de Recherche Saint-Antoine, Sorbonne Université - Faculté Saint Antoine, Paris, France; Department of Virology, GHU Paris-Est, Assistance Publique - Hôpitaux de Paris, Paris, France.
Ann Oncol. 2022 Nov;33(11):1134-1148. doi: 10.1016/j.annonc.2022.08.001. Epub 2022 Aug 10.
ERBB2 is the most prominent therapeutic target in gastroesophageal adenocarcinoma (GEA). For two decades, trastuzumab was the only treatment available for GEA overexpressing ERBB2. Several drugs showing evidence of efficacy over or in complement to trastuzumab in breast cancer failed to show clinical benefit in GEA. This resistance to anti-ERBB2 therapy is peculiarly recurrent in GEA and is mostly due to tumor heterogeneity with the existence of low expressing ERBB2 tumor clones and loss of ERBB2 over time. The development of new ERBB2 testing strategies and the use of antibody-drug conjugates having a bystander effect are providing new tools to fight heterogeneity in ERBB2-positive GEA. Co-amplifications of tyrosine kinase receptors, alterations in mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K) signaling pathways and in proteins controlling cell cycle are well known to contribute resistance to anti-ERBB2 therapy, and they can be targeted by dual therapy. Recently described, NF1 mutations are responsible for Ras phosphorylation and activation and can also be targeted by MEK/ERK inhibition along with anti-ERBB2 therapy. Multiple lines of evidence suggest that immune mechanisms involving antibody-dependent cell-mediated cytotoxicity are preponderant over intracellular signaling in anti-ERBB2 therapy action. A better comprehension of these mechanisms could leverage immune action of anti-ERBB2 therapy and elucidate efficacy of combinations associating immunotherapy and anti-ERBB2 therapy, as suggested by the recent intermediate positive results of the KEYNOTE-811 trial.
ERBB2 是胃食管腺癌（GEA）中最突出的治疗靶点。二十年来，曲妥珠单抗是唯一可用于过表达 ERBB2 的 GEA 的治疗方法。在乳腺癌中显示出比曲妥珠单抗更有效或互补作用的几种药物未能在 GEA 中显示出临床获益。这种对抗 ERBB2 治疗的耐药性在 GEA 中特别常见，主要是由于肿瘤异质性，存在低表达 ERBB2 的肿瘤克隆，并且随着时间的推移 ERBB2 丢失。新的 ERBB2 检测策略的发展和使用具有旁观者效应的抗体药物偶联物为对抗 ERBB2 阳性 GEA 的异质性提供了新的工具。酪氨酸激酶受体的共扩增、丝裂原活化蛋白激酶（MAPK）和磷酸肌醇-3-激酶（PI3K）信号通路以及控制细胞周期的蛋白质的改变，众所周知会导致抗 ERBB2 治疗耐药，并且可以通过双重治疗来靶向这些改变。最近描述的 NF1 突变负责 Ras 磷酸化和激活，并且可以与抗 ERBB2 治疗一起通过 MEK/ERK 抑制来靶向。多项证据表明，涉及抗体依赖性细胞介导的细胞毒性的免疫机制在抗 ERBB2 治疗作用中比细胞内信号传导更为重要。更好地理解这些机制可以利用抗 ERBB2 治疗的免疫作用，并阐明免疫治疗和抗 ERBB2 治疗联合的疗效，正如最近 KEYNOTE-811 试验的中间阳性结果所表明的那样。
