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Depatuxizumab mafodotin (ABT-414)-induced glioblastoma cell death requires EGFR overexpression, but not EGFRY1068 phosphorylation
Molecular Cancer Therapeutics ( IF 5.3 ) Pub Date : 2020-05-05 , DOI: 10.1158/1535-7163.mct-19-0609
Caroline von Achenbach 1 , Manuela Silginer 1 , Vincent Blot 2 , William A Weiss 3 , Michael Weller 1
Affiliation  

Glioblastomas commonly (40%) exhibit epidermal growth factor receptor (EGFR) amplification; half of these tumors carry the EGFRvIII deletion variant characterized by an in-frame deletion of exons 2–7, resulting in constitutive EGFR activation. Although EGFR tyrosine kinase inhibitors had only modest effects in glioblastoma, novel therapeutic agents targeting amplified EGFR or EGFRvIII continue to be developed. Depatuxizumab mafodotin (ABT-414) is an EGFR-targeting antibody–drug conjugate consisting of the mAb 806 and a toxic payload, monomethyl auristatin F. Because glioma cell lines and patient-derived glioma-initiating cell models expressed too little EGFR in vitro to be ABT-414–sensitive, we generated glioma sublines overexpressing EGFR or EGFRvIII to explore determinants of ABT-414–induced cell death. Overexpression of EGFRvIII induces sensitization to ABT-414 more readily than overexpression of EGFR in vitro and in vivo. Exposure to ABT-414 in vivo eliminated EGFRvIII-expressing tumor cells, and recurrent tumors were devoid of EGFRvIII expression. There is no bystander killing of cells devoid of EGFR expression. Surprisingly, either exposure to EGF or to EGFR tyrosin kinase inhibitors reduce EGFR protein levels and are thus not strategies to promote ABT-414–induced cell killing. Furthermore, glioma cells overexpressing kinase-dead EGFR or EGFRvIII retain binding of mAb 806 and sensitivity to ABT-414, allowing to dissociate EGFR phosphorylation from the emergence of the “active” EGFR conformation required for ABT-414 binding. The combination of EGFR-targeting antibody–drug conjugates with EGFR tyrosine kinase inhibitors carries a high risk of failure. Promoting EGFR expression rather than phosphorylation should result in glioblastoma cell sensitization to ABT-414.

中文翻译:

Depatuxizumab mafodotin (ABT-414) 诱导的胶质母细胞瘤细胞死亡需要 EGFR 过表达,但不需要 EGFRY1068 磷酸化

胶质母细胞瘤通常 (40%) 表现出表皮生长因子受体 (EGFR) 扩增;这些肿瘤中有一半携带 EGFRvIII 缺失变体,其特征是外显子 2-7 框内缺失,导致组成型 EGFR 激活。尽管 EGFR 酪氨酸激酶抑制剂对胶质母细胞瘤的作用不大,但仍在继续开发针对扩增的 EGFR 或 EGFRvIII 的新型治疗剂。Depatuxizumab mafodotin (ABT-414) 是一种靶向 EGFR 的抗体-药物偶联物,由 mAb 806 和有毒负载单甲基 auristatin F 组成。对 ABT-414 敏感,我们生成了过表达 EGFR 或 EGFRvIII 的神经胶质瘤亚系,以探索 ABT-414 诱导的细胞死亡的决定因素。在体外和体内,EGFRvIII的过表达比EGFR的过表达更容易诱导对ABT-414的敏化。体内暴露于 ABT-414 消除了表达 EGFRvIII 的肿瘤细胞,并且复发肿瘤没有 EGFRvIII 表达。没有 EGFR 表达的细胞不会被旁观者杀死。令人惊讶的是,暴露于 EGF 或 EGFR 酪氨酸激酶抑制剂会降低 EGFR 蛋白水平,因此不是促进 ABT-414 诱导的细胞杀伤的策略。此外,过表达激酶死亡 EGFR 或 EGFRvIII 的神经胶质瘤细胞保留了 mAb 806 的结合和对 ABT-414 的敏感性,允许将 EGFR 磷酸化与 ABT-414 结合所需的“活性”EGFR 构象的出现分离。EGFR 靶向抗体-药物偶联物与 EGFR 酪氨酸激酶抑制剂的组合具有很高的失败风险。促进 EGFR 表达而不是磷酸化会导致胶质母细胞瘤细胞对 ABT-414 敏感。
更新日期:2020-05-05
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