The
epidermal growth factor receptor (EGFR), expressed in
adrenocorticotrophic hormone (
ACTH)-secreting pituitary adenomas causing
Cushing disease, regulates
ACTH production and corticotroph proliferation. To elucidate the utility of EGFR as a therapeutic target for
Cushing disease, we generated transgenic (Tg) mice with corticotroph-specific human EGFR expression (corti-EGFR-Tg) using a newly constructed corticotroph-specific promoter. Pituitary-specific EGFR expression was observed by 2.5 months, and aggressive
ACTH-secreting pituitary adenomas with features of Crooke's cells developed by 8 months with 65% penetrance observed. Features consistent with the Cushing phenotype included elevated plasma
ACTH and
corticosterone levels, increased
body weight,
glucose intolerance, and enlarged adrenal cortex.
Gefitinib, an EGFR
tyrosine kinase inhibitor, suppressed
tumor POMC expression and downstream EGFR
tumor signaling, and
ACTH and
corticosterone levels were attenuated by 80% and 78%, respectively. Both E2F1 and phosphorylated Ser-337 E2F1 were increased in corti-EGFR-Tg mice and also colocalized with human
POMC (hPOMC) in human pituitary corticotroph
tumor samples. EGFR inhibition reversed E2F1 activity in vivo, whereas E2F1 inhibition suppressed
POMC and
ACTH in cultured human
pituitary tumor cells. The corti-EGFR-Tg phenotype recapitulates
ACTH-secreting pituitary adenomas and
Cushing disease, validating the relevance of EGFR to corticotroph
tumorigenesis. E2F1 is identified as a promising corticotroph-specific target for
ACTH-dependent
Cushing disease.