Role of tyrosine kinase inhibitors in the treatment of pituitary tumours: from bench to bedside.
Role of tyrosine kinase inhibitors in the treatment of pituitary tumours: from bench to bedside.
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DOI：
10.1097/med.0000000000000344
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发表时间：
2017-08
期刊：
影响因子：
--
通讯作者：
Cooper O
中科院分区：
文献类型：
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作者：
Ben-Shlomo A;Cooper O
侵袭性垂体瘤的治疗往往不能达到最佳的肿瘤控制，并导致显著的发病率。乳营养和皮质营养来源的肿瘤表达ErbB受体和配体，USP8突变改变EGFR降解，与库欣病（CD）的发病机制有关。EGFR酪氨酸激酶抑制剂（TKI）治疗已成为侵袭性催乳素瘤和CD患者的潜在新治疗方法。使用EGFR或HER2驱动的PRL启动子，转基因小鼠产生对TKI抑制有反应的大肿瘤。在人促皮质细胞原代培养中，用pan-ErbB TKI卡奈替尼和EGFR TKI吉非替尼治疗可抑制POMC mRNA和USP8突变，在多达三分之二的CD中检测到，可能是这些肿瘤中EGFR信号增加的基础。人催乳素瘤具有与攻击性行为相关的ErbB受体表达差异，一项正在进行的临床试验数据表明，耐药催乳素瘤可能对EGFR TKI拉帕替尼有反应。临床前和临床模型证实了EGFR通路在促皮质性和嗜乳性腺瘤中的作用。虽然需要进一步的研究，但迄今为止的结果表明，靶向ErbB途径可能是侵袭性垂体肿瘤患者的有效治疗方法。
Treatment of aggressive pituitary tumors often yields suboptimal control of the tumor and confers significant morbidity. Lactotroph and corticotroph derived tumors express ErbB receptors and ligands, and mutations in USP8, which alters EGFR degradation, have been implicated in Cushing disease (CD) pathogenesis. EGFR tyrosine kinase inhibitor (TKI) therapy has emerged as a potential new therapeutic approach for patients with aggressive prolactinomas and CD. Using EGFR or HER2 driven PRL promoters, transgenic mice develop large tumors that respond to TKI inhibition. In human corticotroph primary cultures, treatment with the pan-ErbB TKI canertinib as well as the EGFR TKI gefitinib suppresses POMC mRNA, and USP8 mutations, detected in up to two-thirds of CD, may underlie the increase in EGFR signaling in these tumors. Human prolactinomas have differential ErbB receptor expression associated with aggressive behavior and data from an ongoing clinical trial suggest that resistant prolactinomas may respond to the EGFR TKI lapatinib. Preclinical and clinical models substantiate the role of the EGFR pathway in corticotroph and lactotroph adenomas. Although further study is needed, results to date suggest targeting the ErbB pathway may be an effective therapeutic approach for patients with aggressive pituitary tumors.