Glioblastoma cancer stem cells: response to epidermal growth factor receptor kinase inhibitors

Glioblastoma (GBM) is the most common and aggressive neoplasia of the central nervous system in adults. Despite continued improvements in surgery, chemotherapy, and radiotherapy, clinical outcome is still dismal and better understanding of GBM biology is needed to develop novel therapies. Recent studies have demonstrated the existence of a small subpopulation of cells with stem-like features termed cancer stem cells (CSCs) in several human cancers, including GBM. CSCs are slow growing, self-renewable and highly tumorigenic, give rise to progeny of multiple lineages, and are chemo-radio-resistant, often expressing high levels of multidrug resistance and drug efflux genes. According to CSC hypothesis, current therapies are cytotoxic to the bulk of highly proliferative tumor cells but fail to kill the relatively quiescent and resistant CSC subpopulation, thus allowing these cells to survive and induce tumor recurrence. These characteristics allow GBM CSCs to survive cytotoxic therapies and drive tumor recurrence. The epidermal growth factor receptor (EGFR/HER1) belongs to the receptor tyrosine kinase (TK) family that regulates cell proliferation, survival, differentiation and motility. Overexpression of EGFR occurs in several tumors, including GBM, correlates with increased cell proliferation, decreased apoptosis, and a poorer prognosis, sustaining cancer development and progression. Small-molecules targeting EGFR-TK (TK inhibitors, TKIs) are the most clinically developed EGFR targeted-therapies for the treatment of GBM. We reported that cultures enriched in CSC isolated from human GBMs undergo growth arrest and cell death in the presence of EGFR-TKIs. The high incidence of EGFR overexpression, amplification or co-expression of the mutated, constitutively active EGFRvIII in GBMs raised expectations that treatment with EGFR TKIs, such as gefitinib or erlotinib, would have significant positive effects. This review summarizes current knowledge regarding EGFR molecular abnormalities and dysregulation in high-grade gliomas, the role of CSCs in GBM, and discusses the implications of the CSC hypothesis for the development of future EGFRtargeted therapies for brain tumors.