Signaling via epidermal growth factor receptor (EGFR) exerts a potent proliferative stimulus in cancer cells, but EGFR-targeted kinase inhibitors are readily overcome by a number of drug resistance mechanisms that have rendered sustained clinical benefit elusive. Here, Jameson and colleagues identify novel intragenic enhancers of EGFR expression in both glioblastoma (GBM) and head and neck squamous cell carcinoma (HNSCC) which are activated by the transcription factor AP-1 and bromodomain and extra-terminal (BET) epigenetic readers. Genetic disruption of enhancer sequences via CRISPR/Cas9 or suppression of enhancer activity with CRISPRi resulted in marked reduction of EGFR expression, and pharmacologic inhibition of AP-1 signaling or BET activity showed efficacy in suppressing both EGFR expression and proliferation in GBM and HNSCC cells. Overall, the study provides novel insight into the biology underlying EGFR expression in EGFR-driven cancers and provides a rationale for targeting epigenetic regulators as a means of sustained EGFR suppression in GBM...

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