Challenges to targeting epidermal growth factor receptor in glioblastoma: escape mechanisms and combinatorial treatment strategies

Abstract

Epidermal growth factor receptor (EGFR) gene amplification and activating mutations are common findings in glioblastomas. EGFR is at the top of a downstream signaling cascade that regulates important characteristics of glioblastoma cells, including cellular proliferation, migration, and survival. Targeting EGFR has therefore been regarded as a promising therapeutic strategy in glioblastoma for decades. However, although various pharmacological inhibitors and anti-EGFR antibodies are available, the antiglioma activity of these agents has been largely limited to preclinical models, whereas their administration to glioblastoma patients was characterized by lack of clinical benefit. Comprehensive efforts have been made within the last years to understand the underlying mechanisms that confer resistance to EGFR inhibition in glioma cells. The absence of well-known mutations that predict response to EGFR tyrosine kinase inhibitors (TKIs) in gliomas as well as the presence of redundant and alternative compensatory pathways are among the most important escape mechanisms that prevent potent antiglioma effects of EGFR-targeting drugs. Accordingly, an increasing number of in vitro and in vivo studies are aimed at overcoming this resistance by combinatorial approaches using anti-EGFR treatment together with one or more additional drugs. Novel insights into the molecular mechanisms mediating resistance to anti-EGFR treatment and promising combinatorial approaches may help to better define a future role for EGFR inhibition in the treatment of glioblastoma.

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).…”

A wide spectrum of EGFR mutations in glioblastoma is detected by a single clinical oncology targeted next-generation sequencing panel

“…In GBM, EGFR is commonly found to encompass the spectrum of these types of mutations, requiring testing by a multitude of molecular oncology assays to ascertain the full spectrum of mutations (Brennan et al, 2013; TCGA, 2008). Although limited clinical efficacy has been demonstrated so far, amplified and variant EGFR is currently being investigated as a therapeutic target in GBM (Gan et al, 2013; Reardon et al, 2013; Roth and Weller, 2014; Schulte et al, 2013). The EGFR variant, EGFRvIII (genomic deletions of exon 2 through 7), is a constitutively active form of EGFR that has attracted much attention as a GBM therapeutic target.…”

“…The EGFR variant, EGFRvIII (genomic deletions of exon 2 through 7), is a constitutively active form of EGFR that has attracted much attention as a GBM therapeutic target. While testing for EGFRvIII is not performed during routine neuropathological workup of GBM, mutational status is used by some clinicians for the inclusion of ongoing vaccine or antibody trials targeting EGFRvIII (Gan et al, 2013; Roth and Weller, 2014). …”

Bi-specific molecule against EGFR and death receptors simultaneously targets proliferation and death pathways in tumors

“…While targeting over-expressed and mutated EGFR on tumor cells is a promising approach it has provided very limited clinical benefit in the setting of glioblastoma 29 . There are several EGFR mediated signaling resistance mechanisms that have become evident that potentially reduce efficacy of DR targeted therapeutic agents.…”