Overexpression of the EGF receptor (EGFR), a cell surface protein that transmits growth-promoting signals, contributes to the proliferation and survival of many types of cancer cells. A number of targeted cancer drugs seek to disable the receptor. A team led by Ludwig San Diego’s Frank Furnari reported in an August paper in Molecular Cancer Research two novel enhancers of gene expression located within the first intron—a noncoding stretch of DNA within a gene—of the EGFR gene in models of the brain cancer glioblastoma and head and neck squamous cell carcinoma. Frank and graduate student Nathan Jameson characterized these novel enhancers, finding that their effects are mediated by the AP-1 family of transcription factors (which control gene expression) and BET bromodomain proteins. Genetic or pharmacologic disruption of interactions between AP1 or BET with the enhancers suppress EGF receptor expression, providing a rationale for targeting these interactions to treat EGFR-positive tumors, which can be highly dependent on the receptor’s signaling. AP1 and BET bromodomain proteins can be targeted by either existing or experimental drugs.
This article appeared in the November 2019 issue of Ludwig Link. Click here to download a PDF (1 MB).