Depatuxizumab Mafodotin (ABT-414)-induced Glioblastoma Cell Death Requires EGFR Overexpression, but not EGFRY1068 Phosphorylation.

Abstract

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.

• Authors: Caroline von Achenbach, Manuela Silginer, Vincent Blot, William A Weiss, Michael Weller
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 19 Issue 6 Pg. 1328-1339 (06 2020) ISSN: 1538-8514 [Electronic] United States
• PMID: 32371586 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• ABT-414
• Antibodies, Monoclonal, Humanized
• Immunoconjugates
• EGFR protein, human
• ErbB Receptors

Topics

• Animals
• Antibodies, Monoclonal, Humanized (pharmacology)
• Apoptosis
• Cell Proliferation
• ErbB Receptors (genetics, metabolism)
• Glioblastoma (drug therapy, genetics, metabolism, pathology)
• Humans
• Immunoconjugates (pharmacology)
• Mice
• Mice, Nude
• Mutation
• Phosphorylation
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays