EGFR amplification and EGFRvIII predict and participate in TAT-Cx43_266-283 antitumor response in preclinical glioblastoma models

Fecha de publicación: 20/03/2024 Fecha Ahead of Print: 01/03/2024

Autores de IBSAL

• Andrea Álvarez Vázquez

  Autor

• Laura San Segundo Payo

  Autor

• María Del Pilar Cerveró García

  Autor

• Raquel Flores Hernández

  Autor

• Claudia Ollauri Ibáñez

  Autor

• 

  Aránzazu Tabernero Urbieta

  Autor

Autores ajenos a IBSAL

• Segura-Collar, B
• Hubert, CG
• Morrison, G
• Pollard, SM
• Lathia, JD
• Sánchez-Gómez, P

Grupos

• NEUR-06 - Neurobioquímica

  

  Investigador Principal

  Aránzazu Tabernero Urbieta

Abstract

Background Glioblastoma (GBM) commonly displays epidermal growth factor receptor (EGFR) alterations (mainly amplification and EGFRvIII) and TAT-Cx43(266-283) is a Src-inhibitory peptide with antitumor properties in preclinical GBM models. Given the link between EGFR and Src, the aim of this study was to explore the role of EGFR in the antitumor effects of TAT-Cx43(266-283.) Methods The effect of TAT-Cx43(266-283), temozolomide (TMZ) and erlotinib (EGFR inhibitor) was studied in patient-derived GBM stem cells (GSCs) and murine neural stem cells (NSCs) with and without EGFR alterations, in vitro and in vivo. EGFR alterations were analyzed by Western blot (WB) and Fluorescence In Situ Hybridization (FISH) in these cells, and compared with Src activity and survival in GBM samples from TCGA. Results The effect of TAT-Cx43(266-283) correlated with EGFR alterations in a set of patient-derived GSCs and was stronger than that exerted by TMZ and erlotinib. In fact, TAT-Cx43(266-283) only affected NSCs with EGFR alterations, but not healthy NSCs. EGFR alterations correlated with Src activity and poor survival in GBM patients. Finally, tumors generated from NSCs with EGFR alterations, showed a decrease in growth, invasiveness and vascularization after treatment with TAT-Cx43(266-283,) which enhanced the survival of immunocompetent mice. Conclusion Clinically relevant EGFR alterations are predictors of TAT-Cx43(266-283) response and part of its mechanism of action, even in TMZ- and erlotinib-resistant GSCs. TAT-Cx43(266-283) targets NSCs with GBM-driver mutations, including EGFR alterations, in an immunocompetent GBM model in vivo, suggesting a promising effect on GBM recurrence. Together, this study represents an important step towards the clinical application of TAT-Cx43(266-283).

Keywords

• cell-penetrating peptides; EGFR; glioblastoma; NSCs; Src