Targeting epidermal growth factor receptor co‐dependent signaling pathways in glioblastoma. (11th September 2017)

• Record Type: Journal Article
• Authors: Liu, Feng; Mischel, Paul S.
• Is Part Of: Wiley interdisciplinary reviews. Volume 10:Number 1(2018)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2017-09-11
• Subjects: Systems biology -- Periodicals; Medicine -- Periodicals; 610
• DOI: 10.1002/wsbm.1398
• Languages: English
• ISSNs: 1939-5094

Abstract

Abstract : The epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase (RTK) that is critical for normal development and function. EGFR is also amplified or mutated in a variety of cancers including in nearly 60% of cases of the highly lethal brain cancer glioblastoma (GBM). EGFR amplification and mutation reprogram cellular metabolism and broadly alter gene transcription to drive tumor formation and progression, rendering EGFR as a compelling drug target. To date, brain tumor patients have yet to benefit from anti‐EGFR therapy due in part to an inability to achieve sufficient intratumoral drug levels in the brain, cultivating adaptive mechanisms of resistance. Here, we review an alternative set of strategies for targeting EGFR‐amplified GBMs, based on identifying and targeting tumor co‐dependencies shaped both by aberrant EGFR signaling and the brain's unique biochemical environment. These approaches may include highly brain‐penetrant drugs from non‐cancer pipelines, expanding the pharmacopeia and providing promising new treatments. We review the molecular underpinnings of EGFR‐activated co‐dependencies in the brain and the promising new treatments based on this strategy. WIREs Syst Biol Med 2018, 10:e1398. doi: 10.1002/wsbm.1398 This article is categorized under: Biological Mechanisms > Cell Signaling Laboratory Methods and Technologies > Genetic/Genomic Methods Translational, Genomic, and Systems Medicine > Translational Medicine Abstract : The epidermal growth factor receptor (EGFR) is a transmembrane protein that transduces intracellular signaling pathways upon the binding with its ligand EGF. In Glioblastoma (GBM), amplified and mutated EGFR (sometimes appearing in extrachromosomal DNA, ecDNA) leads to constitutively active EGFR signaling even in the absence of EGF binding. The resulting hyper‐activated EGFR reprograms the epigenome and metabolic pathways to drive uncontrollable cell proliferation and tumor growth. Targeting these EGFR co‐dependent pathways in GBM may offer new revenues to develop anti‐cancer therapy.