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Targeting epidermal growth factor receptor co‐dependent signaling pathways in glioblastoma

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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.

Structure and function of the epidermal growth factor receptor (EGFR) signaling pathway. The membrane‐bound EGFR can activate three major branches of protein kinase pathway, leading to profound changes in both the cytoplasm and the nucleus to influence cellular phenotype at tissue and organismal levels.
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Studying non‐oncogene co‐dependency provides novel drug targets. (a) Hyperactivated epidermal growth factor receptor (EGFR) signaling activities converge on the elevation of c‐MYC to promote anaerobic glycolysis (Warburg effect) in glioblastoma (GBM) cells. This effect can be suppressed by dual inhibition of PI3K and mTOR inhibitor(s). (b) Amplified and hyperactivated EGFR can also stimulate thousands of distal cis‐regulatory elements called enhancers to promote a cancer‐driving gene expression program. Small molecule compound such as JQ1 can intercept this epigenomic reprogramming activity by inactivating an enhancer‐binding transcription cofactor BRD4. (c) In the brain, hyperactivated EGFR increases cholesterol update in GBM cells. LXR agonist like LXR‐623 suppresses cholesterol update by activating an endogenous cholesterol homeostasis pathway involving IDOL, which degrades low‐density lipoprotein receptor (LDLR), and ABCA1, which transports cholesterol out of the cell.
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Intracellular mechanisms of resistance against epidermal growth factor receptor (EGFR)‐targeted therapy. Anti‐EGFR therapy can be compromised by feedback mechanisms that maintain intracellular receptor tyrosine kinase signaling activities, and by dynamic exchanges between extra‐ and intra‐chromosomal EGFR DNA, which replenishes EGFR expression levels in glioblastoma cells.
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Genetic alternations of epidermal growth factor receptor (EGFR) in cancers. (a) The alternation frequency of EGFR across cancers surveyed by The Cancer Genome Atlas consortium (www.cbioportal.com). (b) In primary glioblastoma, EGFR amplification mutation often occur in the same tumor.
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Laboratory Methods and Technologies > Genetic/Genomic Methods
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In the Spotlight

Jens Nielsen

Jens Nielsen
is a Professor in the Department of Biology and Biological Engineering at Chalmers University of Technology in Göteborg, Sweden. His research focus is on systems biology of metabolism. The yeast Saccharomyces cerevisiae is the lab’s key organism for experimental research, but they also work with Aspergilli oryzae.

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