Highlighting the potential of aptamer-based strategy to treat EGFRvIII-positive glioblastoma

Abstract

Epidermal growth factor receptor variant III (EGFRvIII) is the most common EGFR mutant found in glioblastoma (GBM). Due to a truncation of large portion of the extracellular region, EGFRvIII is unable to bind any ligand and constitutively signals to downstream effector molecules. It is tumor-specific, highly oncogenic and usually co-expressed with EGFR wild type (EGFRwt). EGFR tyrosine kinase inhibitors (TKIs) have proven ineffective in GBM and different mechanisms account for the occurrence of resistance to such inhibitors. Among these, EGFR TKIs induce a switch to platelet-derived growth factor receptor β (PDGFRβ) expression and signaling, thus rendering the tumors addicted to such receptor for continued growth and resistance to treatment. In our recent investigation, we showed the ability of a nuclease-resistant RNA aptamer, named CL4, to bind and inhibit EGFRvIII thus hampering proliferation, migration and invasion of EGFRvIII-positive GBM cells. Importantly, both CL4 and EGFR TKIs cooperate with a previously validated anti-PDGFRβ aptamer in inhibiting cell growth. Here, we highlight the potential of the EGFRvIII aptamer to hamper the EGFRvIII functional interplay with other receptor tyrosine kinases (RTKs) and cell surface proteins responsible for GBM development and progression. The utility of CL4 as targeting ligand for drug-delivery approaches is also discussed. Overall, aptamer-based molecules have significant implications for managing GBM in the near future.