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

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.

Figure 1. Structure and function of the 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.

Figure 2. Genetic alternations of EGFR in cancers

(a) The alternation frequency of EGFR across cancers surveyed by The Cancer Genome Atlas consortium (www.cbioportal.com). (b) In primary GBM, EGFR amplification mutation often occur in the same tumor.

Figure 3. Intracellular mechanisms of resistance against EGFR-targeted therapy

Anti-EGFR therapy can be compromised by feedback mechanisms that maintain intracellular RTK signaling activities, and by dynamic exchanges of between extra- and intra-chromosomal EGFR DNA, which replenishes EGFR expression levels in GBM cells.

Figure 4. Studying non-oncogene co-dependency provides novel drug targets

(a) Hyperactivated EGFR signaling activities converge on the elevation of c-MYC to promote anaerobic glycolysis (Warburg effect) in 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 LDLR, and ABCA1, which transports cholesterol out of the cell.