EGFR-Targeted Therapy in Malignant Glioma: Novel Aspects and Mechanisms of Drug Resistance

Abstract

Glioblastoma, GBM, is the most frequent brain malignancy in adults. Patients with these tumors survive only, approximately, one year after diagnosis and rarely survive beyond two years. This poor prognosis is, in part, due to our insufficient understanding of the complex aggressive nature of these tumors and the lack of effective therapy. In GBM, over-expression of EGFR and/or its constitutively activated variant EGFRvIII is a major characteristic and is associated with tumorigenesis and more aggressive phenotypes, such as, invasiveness and therapeutic resistance. Consequently, both have been major targets for GBM therapy, however, clinical trials of EGFRand EGFRvIII-targeted therapies have yielded unsatisfactory results and the molecular basis for the poor results is still unclear. Thus, in this review, we will summarize results of recent clinical trials and recent advances made in the understanding of the EGFR/EGFRvIII pathways with a key focus on those associated with intrinsic resistance of GBM to EGFR-targeted therapy. For example, emerging evidence indicates an important role that PTEN plays in predicting GBM response to EGFR-targeted therapy. Aberrant Akt/mTOR pathway has been shown to contribute to the resistant phenotype. Also, several studies have reported that EGFR/EGFRvIII's cross-talk with the oncogenic transcription factorSTAT3 and receptor tyrosine kinases, (c-Met and PDGFR) potentially lead to GBM resistance to anti-EGFR therapy. Other emerging mechanisms, including one involving HMG-CoA reductase, will also be discussed in this mini-review. These recent findings have provided new insight into the highly complex and interactive nature of the EGFR pathway and generated rationales for novel combinational targeted therapies for these tumors.

Mass spectrometry‐based secretome analysis of non‐small cell lung cancer cell lines

“…The EGFR‐signaling pathway is one of the most dysregulated pathways in human cancers . In the last years, tyrosine kinase inhibitors have been used to treat various cancer types, such as breast cancer, NSCLC, colorectal carcinoma, and others . NSCLC seems to be responsive to tyrosine kinase inhibitor treatment, but unfortunately, most NSCLC patients develop a resistance to tyrosine kinase inhibitors, such as erlotinib .…”

Nuclear epidermal growth factor receptor and p16 expression in head and neck squamous cell carcinoma

“…However, additional data suggesting the unique subcellular roles of EGFR are now emerging 7, 8. High levels of nuclear EGFR are detected in many tumors, including adrenocorticoid, breast, bladder, skin, thyroid, glioma, and oropharynx tumors 9–12. While localized in the nucleus, EGFR functions as a transcriptional regulator by binding to promoters that enhance transcription of cyclin D1, inducible nitric oxide synthase, B‐Myb, cyclooxygenase‐2, and aurora A 13–16.…”

EGFR and EGFRvIII interact with PUMA to inhibit mitochondrial translocalization of PUMA and PUMA-mediated apoptosis independent of EGFR kinase activity

“…Small molecule EGFR inhibitors and monoclonal anti-EGFR antibodies have been evaluated clinically for the efficacy against GBM patients both as single agents and in combination with chemotherapeutic agents [11]. These therapies have, however, demonstrated only modest effects [12; 13; 14; 15].…”