EGFR as a therapeutic target for human, canine, and mouse ACTH-secreting pituitary adenomas
EGFR as a therapeutic target for human, canine, and mouse ACTH-secreting pituitary adenomas
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DOI：
10.1172/jci60417
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发表时间：
2011-12-01
影响因子：
15.9
通讯作者：
Melmed, Shlomo
中科院分区：
文献类型：
--
作者：
Fukuoka, Hidenori;Cooper, Odelia;Melmed, Shlomo
库欣病是由于垂体前叶促肾上腺皮质激素（ACTH）分泌细胞产生的腺瘤导致垂体释放过量ACTH的疾病。促肾上腺皮质激素分泌性垂体腺瘤导致高皮质醇血症，并导致显著的发病率和死亡率。针对垂体的药物大多无效，需要新的治疗选择。由于这些肿瘤表达EGFR，我们测试了EGFR是否可能为库欣病提供治疗靶点。在这里，我们表明，在手术切除的人类和犬促肾上腺皮质激素细胞培养的肿瘤，阻断EGFR抑制阿黑皮素原（POMC），促肾上腺皮质激素前体的表达。在小鼠促肾上腺皮质激素细胞EGFR转染子中，ACTH分泌增强，EGF增加Pomc启动子活性，这种作用依赖于MAPK。用EGFR酪氨酸激酶抑制剂吉非替尼阻断EGFR活性，可减弱Pomc表达，抑制促肾上腺皮质激素细胞肿瘤细胞增殖，并诱导细胞凋亡。由于在犬和人促肾上腺皮质激素细胞肿瘤中观察到EGFR主要在细胞核中表达，因此我们优先将EGFR靶向小鼠促肾上腺皮质激素细胞核，这导致更高的Pomc表达和ACTH分泌，而这两者都被吉非替尼抑制。在无胸腺裸鼠中，EGFR过表达增强了促肾上腺皮质激素分泌肿瘤的生长，并进一步升高了血清皮质酮水平。吉非替尼治疗降低了肿瘤大小和皮质酮水平;它还逆转了高皮质醇血症的体征，包括葡萄糖水平升高和网膜脂肪过多。这些结果表明，抑制EGFR信号转导可能是治疗库欣病的一种新策略。
Cushing disease is a condition in which the pituitary gland releases excessive adrenocorticotropic hormone (ACTH) as a result of an adenoma arising from the ACTH-secreting cells in the anterior pituitary. ACTH-secreting pituitary adenomas lead to hypercortisolemia and cause significant morbidity and mortality. Pituitary-directed medications are mostly ineffective, and new treatment options are needed. As these tumors express EGFR, we tested whether EGFR might provide a therapeutic target for Cushing disease. Here, we show that in surgically resected human and canine corticotroph cultured tumors, blocking EGFR suppressed expression of proopiomelanocortin (POMC), the ACTH precursor. In mouse corticotroph EGFR transfectants, ACTH secretion was enhanced, and EGF increased Pomc promoter activity, an effect that was dependent on MAPK. Blocking EGFR activity with gefitinib, an EGFR tyrosine kinase inhibitor, attenuated Pomc expression, inhibited corticotroph tumor cell proliferation, and induced apoptosis. As predominantly nuclear EGFR expression was observed in canine and human corticotroph tumors, we preferentially targeted EGFR to mouse corticotroph cell nuclei, which resulted in higher Pomc expression and ACTH secretion, both of which were inhibited by gefitinib. In athymic nude mice, EGFR overexpression enhanced the growth of explanted ACTH-secreting tumors and further elevated serum corticosterone levels. Gefitinib treatment decreased both tumor size and corticosterone levels; it also reversed signs of hypercortisolemia, including elevated glucose levels and excess omental fat. These results indicate that inhibiting EGFR signaling may be a novel strategy for treating Cushing disease.