Glioblastoma Cancer Stem Cells: Response to Epidermal Growth Factor Receptor Kinase Inhibitors

Abstract

Glioblastoma (GBM) is the most common and aggressive neoplasia of thecentral nervous system in adults. Despite continued improvements insurgery, chemotherapy, and radiotherapy, clinical outcome is stilldismal and better understanding of GBM biology is needed to developnovel therapies. Recent studies have demonstrated the existence of asmall subpopulation of cells with stem-like features termed cancer stemcells (CSCs) in several human cancers, including GBM. CSCs are slowgrowing, self-renewable and highly tumorigenic, give rise to progeny ofmultiple lineages, and are chemo-radio-resistant, often expressing highlevels of multidrug resistance and drug efflux genes. According to CSChypothesis, current therapies are cytotoxic to the bulk of highlyproliferative tumor cells but fail to kill the relatively quiescent andresistant CSC subpopulation, thus allowing these cells to survive andinduce tumor recurrence. These characteristics allow GBM CSCs to survivecytotoxic therapies and drive tumor recurrence. The epidermal growthfactor receptor (EGFR/HER1) belongs to the receptor tyrosine kinase (TK)family that regulates cell proliferation, survival, differentiation andmotility. Overexpression of EGFR occurs in several tumors, includingGBM, 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 mostclinically developed EGFR targeted-therapies for the treatment of GBM.We reported that cultures enriched in CSC isolated from human GBMsundergo growth arrest and cell death in the presence of EGFR-TKIs. Thehigh incidence of EGFR overexpression, amplification or co-expression ofthe mutated, constitutively active EGFRvIII in GBMs raised expectationsthat treatment with EGFR TKIs, such as gefitinib or erlotinib, wouldhave significant positive effects. This review summarizes currentknowledge regarding EGFR molecular abnormalities and dysregulation inhigh-grade gliomas, the role of CSCs in GBM, and discusses theimplications of the CSC hypothesis for the development of futureEGFR-targeted therapies for brain tumors.