ZD6474 suppresses oncogenic RET isoforms in a Drosophila model for type 2 multiple endocrine neoplasia syndromes and papillary thyroid carcinoma
ZD6474 suppresses oncogenic RET isoforms in a Drosophila model for type 2 multiple endocrine neoplasia syndromes and papillary thyroid carcinoma
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DOI：
10.1158/0008-5472.can-04-4561
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发表时间：
2005-05-01
期刊：
影响因子：
11.2
通讯作者：
Cagan, R
中科院分区：
文献类型：
--
作者：
Vidal, M;Wells, S;Cagan, R
遗传性甲状腺髓样癌(MTC)合并多发性内分泌肿瘤(MEN)2A型和2B型及家族性MTC(FMTC)患者存在BET原癌基因突变。大约40%的乳头状甲状腺癌(PTC)患者具有典型的染色体内或染色体外重排，这些重排将无关基因的启动子和NH2末端结构域连接到BET的COOH末端片段。与MEN2A、MEN2B或FMTC相关的RET点突变，或与PTC相关的染色体断裂点和易位，通常激活BET受体酪氨酸激酶(RTK)。Bit激酶抑制剂可能对遗传性MTC患者有益，目前尚无有效的化疗或放射治疗。最近，低分子酪氨酸激酶抑制剂ZD6474被发现在培养的细胞系中阻断RET来源的癌蛋白的酶活性。我们通过将致癌形式的BET靶向于发育中的果蝇眼睛，建立了一种针对MEN2A和MEN2B疾病的果蝇模型。在这里，我们表明，当口服ZD6474时，在这个体内模型的背景下，ZD6474抑制RET介导的表型。重要的是，ZD6474表现出高效和极低的毒性。该化合物未能显著抑制另一种RTK的激活形式，即果蝇表皮生长因子受体，也没有抑制RET/RAS途径下游成分的活性。我们的结果支持这样一种观点，即针对BET致癌形式的组织靶向化学激酶抑制剂，如ZD6474，是一种有用的BET依赖型癌症的治疗策略。
Patients with hereditary medullary thyroid carcinoma (MTC) associated with multiple endocrine neoplasia (MEN) types 2A and 2B and familial MTC (FMTC) have mutations in the BET proto-oncogene. Approximately 40 percent of patients with Papillary thyroid carcinoma (PTC) typically have either intrachromosomal or extrachromosomal rearrangements that join the promoter and NH2-terminal domains of unrelated genes to the COOH-terminal fragment of BET. The RET point mutations associated with MEN2A, MEN2B, or FMTC, or the chromosomal breakpoints and translocations associated with PTC, typically activate the BET receptor tyrosine kinase (RTK). BET kinase inhibitors are likely to be beneficial for patients with hereditary MTC, where currently there is no effective chemotherapy or radiation therapy. Recently, the low molecular weight tyrosine kinase inhibitor ZD6474 was found to block the enzymatic activity of RET-derived oncoproteins in cultured cell lines. We have developed a Drosophila model for MEN2A and MEN2B diseases by targeting oncogenic forms of BET to the developing Drosophila eye. Here we show that, when fed orally, ZD6474 suppressed RET-mediated phenotypes within the context of this in vivo model. Importantly, ZD6474 showed high efficacy and very low toxicity. This compound failed to significantly suppress an activated form of another RTK, the Drosophila epidermal growth factor receptor, nor did it suppress the activity of downstream components of the RET/Ras pathway. Our results support the view that targeting chemical kinase inhibitors such as ZD6474 to tissues with oncogenic forms of BET is a useful treatment strategy for BET-dependent carcinomas.