Targeting a Glioblastoma Cancer Stem-Cell Population Defined by EGF Receptor Variant III

Abstract

The relationship between mutated proteins and the cancer stem cell population is unclear. Glioblastoma tumors frequently express EGFRvIII, an EGFR variant that arises via gene rearrangement and amplification. However, expression of EGFRvIII is restricted despite the prevalence of the alteration. Here we show that EGFRvIII is highly co-expressed with CD133 and that EGFRvIII+/CD133+ defines the population of cancer stem cells with the highest degree of self-renewal and tumor initiating ability. EGFRvIII+ cells are associated with other stem/progenitor markers while markers of differentiation are found in EGFRvIII− cells. EGFRvIII expression is lost in standard cell culture but its expression is maintained in tumor sphere culture, and cultured cells also retain the EGFRvIII+/CD133+ co-expression and self-renewal and tumor initiating abilities. Elimination of the EGFRvIII+/CD133+ population using a bispecific antibody reduced tumorigenicity of implanted tumor cells better than any reagent directed against a single epitope. This work demonstrates that a mutated oncogene can have CSC specific expression and be used to specifically target this population.

Epidermal Growth Factor Receptor Variant III (EGFRvIII) Positivity in EGFR-Amplified Glioblastomas: Prognostic Role and Comparison between Primary and Recurrent Tumors

“…Accumulating preclinical evidence has attributed an important function of EGFRvIII-expressing glioblastoma cells in driving tumor heterogeneity and progression by promoting glioma cell proliferation, invasion, angiogenesis, stemness, and therapy resistance in different model systems (36)(37)(38)(39)(40)(41)(42)(43). In addition, several therapeutic approaches targeting overexpressed wild type EGFR protein or specifically EGFRvIII have already entered, or are about to enter clinical evaluation, including peptide-based vaccines (44)(45)(46), chimeric antigen receptor (CAR) T cells (47,48), as well as anti-EGFR antibodybased approaches (22,49,50).…”

Berberine Induces Senescence of Human Glioblastoma Cells by Downregulating the EGFR–MEK–ERK Signaling Pathway

“…Gain of function of EGFR can lead to the upregulation of RAS and PI3K-AKT signaling pathways, and thereby drives cell survival and proliferation (22)(23)(24). We, therefore, tested whether EGFRinitiated pathways are altered in glioblastoma cells treated with berberine.…”

Effective Eradication of Glioblastoma Stem Cells by Local Application of an AC133/CD133-Specific T-cell–Engaging Antibody and CD8 T Cells

“…EGFRvIII-specific T-cell-recruiting antibodies have shown activity against orthotopic EGFRvIII-overexpressing U87 gliomas in immunodeficient mice (38). It has recently been shown that EGFRvIII is associated with GBM-SCs and coexpressed with CD133 as well as other stem cell and progenitor markers (39). EGFRvIII-specific T-cell-recruiting Abs may therefore also induce T-cell-mediated lysis of CSCs, including GBM-SCs, in EGFRvIII þ patients.…”