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Background <p>Glioblastoma (GBM), the most common primary malignant brain tumor in adults, remains uniformly fatal due to the lack of effective targeted therapies. The epidermal growth factor receptor (EGFR) is the most frequently altered receptor tyrosine kinase oncogene in GBM with most alterations impacting the receptor ectodomain function, including gene amplification, mutation, rearrangement, and splicing site changes, which occur in approximately 50% of GBM tumors. Depatuxizumab mafodotin (Depatux-M; ABT-414), an antibody-drug conjugate composed of an EGFR-specific antibody (ABT-806) that recognizes the EGFR ectodomain linked to the cytotoxic agent monomethyl auristatin F, initially showed clinical promise. However, it failed to improve survival in phase III trials, highlighting an urgent need to understand mechanisms of resistance.</p> Methods <p>We generated in vivo ABT-414 resistant GBM models using patient-derived xenografts (PDXs) and performed genomics and transcriptomic profiling, including whole exome sequencing, bulk RNA sequencing, and single-cell RNA sequencing.</p> Results <p>ABT-414-resistant tumors exhibited transcriptional reprogramming characterized by upregulation of synaptic and developmental gene networks and downregulation of biosynthetic processes, indicative of a plastic, therapy-adaptive state. Whole-exome sequencing revealed novel mutations exclusive to resistant tumors, including a recurrent TEK (TIE2) S466I point mutation present in all ABT-414 resistant GBM12 PDX tumors. Functional validation demonstrated that ectopic expression of TEK S466I and TEK WT in PDX models reduced EGFR levels, suggesting a novel feedback mechanism linking TEK signaling to EGFR downregulation and contributes to resistance.</p> Conclusion <p>Our findings demonstrate that resistance to ABT-414 arises through both adaptive transcriptional remodeling and newly acquired genetic alterations. TEK-mediated suppression of EGFR represents a previously unrecognized mechanism of resistance, with potential implications for overcoming antibody-drug conjugate failure in GBM.</p>

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Glioblastoma resistance to EGFR antibody-drug conjugate is driven by transcriptional reprogramming and TEK-induced EGFR suppression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月21日

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  • Mylan R. Blomquist,
  • Teresa M. R. Noviello,
  • Christopher Sereduk,
  • Dustin Grief,
  • Francesca P. Caruso,
  • Ritin Sharma,
  • Krystine Garcia-Mansfield,
  • Patrick Pirrotte,
  • Jean Kloss,
  • Fulvio D’Angelo,
  • Bianca M. Marin,
  • Kendra Porath,
  • Sonia Jain,
  • Benjamin Rabichow,
  • Shannon P. Fortin Ensign,
  • Antonio Iavarone,
  • Antonella Paladino,
  • Jann N. Sarkaria,
  • Joseph C. Loftus,
  • Michele Ceccarelli,
  • Nhan L. Tran

摘要

Background

Glioblastoma (GBM), the most common primary malignant brain tumor in adults, remains uniformly fatal due to the lack of effective targeted therapies. The epidermal growth factor receptor (EGFR) is the most frequently altered receptor tyrosine kinase oncogene in GBM with most alterations impacting the receptor ectodomain function, including gene amplification, mutation, rearrangement, and splicing site changes, which occur in approximately 50% of GBM tumors. Depatuxizumab mafodotin (Depatux-M; ABT-414), an antibody-drug conjugate composed of an EGFR-specific antibody (ABT-806) that recognizes the EGFR ectodomain linked to the cytotoxic agent monomethyl auristatin F, initially showed clinical promise. However, it failed to improve survival in phase III trials, highlighting an urgent need to understand mechanisms of resistance.

Methods

We generated in vivo ABT-414 resistant GBM models using patient-derived xenografts (PDXs) and performed genomics and transcriptomic profiling, including whole exome sequencing, bulk RNA sequencing, and single-cell RNA sequencing.

Results

ABT-414-resistant tumors exhibited transcriptional reprogramming characterized by upregulation of synaptic and developmental gene networks and downregulation of biosynthetic processes, indicative of a plastic, therapy-adaptive state. Whole-exome sequencing revealed novel mutations exclusive to resistant tumors, including a recurrent TEK (TIE2) S466I point mutation present in all ABT-414 resistant GBM12 PDX tumors. Functional validation demonstrated that ectopic expression of TEK S466I and TEK WT in PDX models reduced EGFR levels, suggesting a novel feedback mechanism linking TEK signaling to EGFR downregulation and contributes to resistance.

Conclusion

Our findings demonstrate that resistance to ABT-414 arises through both adaptive transcriptional remodeling and newly acquired genetic alterations. TEK-mediated suppression of EGFR represents a previously unrecognized mechanism of resistance, with potential implications for overcoming antibody-drug conjugate failure in GBM.