TGFBeta Receptor Mutations in Cancer and Other Diseases

描述（由申请人提供）：转化生长因子-？（TGF?）控制组织稳态，协调对组织损伤和修复的反应。肿瘤逃离TGF？但可以激活组织修复功能以增强其侵袭/转移表型。这个概念导致了TGF？用于癌症治疗的途径拮抗剂。然而，TGF？“通路成瘾”是这些药物临床应用开发的主要障碍。我们的中心假设是TGF？受体基因突变是通路成瘾的指示，因此可以预测对拮抗剂的反应。超过40种癌症相关的I型或-II型TGF？受体基因（TGFBR1, TGFBR2）已被鉴定。我们最近发现其中一些成分激活了T？R-II受体激酶，一方面与Smad2/3激活的丧失有关，另一方面与Smad1/5的重新激活和高度运动性和侵袭性表型有关。此外，选择性T？R-ll激酶抑制剂逆转了转化的表型。与此同时，马凡氏综合征样遗传疾病最近被归因于TGFBR1或TGFBR2的突变。这些突变也赋予患者成纤维细胞和血管平滑肌细胞活化表型。此外，与癌症和马范氏样综合征相关的TGFBR突变之间存在惊人的相似之处：(1)TGFBR2基因突变比TGFBR1基因突变更常见；(2) TGFBR2突变聚集在T？R-II激酶;(3)许多在人类癌症中突变的TGFBR2与马凡氏样综合征相关的TGFBR2以及D. melanogaster的TGFBR2同源基因一致。因此，将这三个不同来源的实验证据汇聚在一起，有力地支持了TGF？受体基因突变可导致异常活化的细胞表型。我们的具体目标是：1。利用结构生物学方法预测TGFBR2基因突变对其与其他蛋白相互作用的影响；2. 利用遗传分析确定黑腹龙TGFBR2基因突变赋予功能获得表型；3. 确定TGFBR2基因突变对TGF？哺乳动物细胞中的信号传导；4. 利用选择性化学物质T？R激酶抑制剂对功能获得性TGFBR2突变细胞的潜在治疗作用。这些研究特别重要，因为TGF？拮抗剂正处于治疗（转移性）癌症和纤维化疾病的（预）临床开发阶段。因此，我们的研究不仅可以为TGFBR致病突变的分子病理生物学提供精确的认识，还可以为TGF？用于癌症和其他疾病的途径抑制剂。

DESCRIPTION (provided by applicant): Transforming Growth Factor-? (TGF?) controls tissue homeostasis and orchestrates the response to tissue injury and repair. Cancers escape from TGF? 's homeostatic function but can activate the tissue repair function to enhance their invasive/metastatic phenotype. This concept has led to the development of TGF? pathway antagonists for cancer treatment. However, the absence of biomarkers for TGF? "pathway addiction" is a major roadblock in the development of these agents for clinical use. Our central hypothesis is that TGF? receptor gene mutations are indicative of pathway addiction and, therefore, predictive of response to antagonists. Over 40 cancer-associated missense mutations of the types I or -II TGF? receptor genes (TGFBR1, TGFBR2) have been identified. We have recently found that some of these constitutively activate the T?R-II receptor kinase, associated with loss of Smad2/3 activation on the one hand, and with de novo activation of Smad1/5 and a highly motile and invasive phenotype on the other. Moreover, treatment with selective T?R-ll kinase inhibitors reversed the transformed phenotype. In parallel, Marfan syndrome-like genetic disorders have recently been attributed to mutations of TGFBR1 or TGFBR2. These mutations also confer an activated phenotype on patient fibroblasts and vascular smooth muscle cells. Moreover, striking parallels exist between cancer- and Marfan-like syndrome-associated TGFBR mutations: (1) TGFBR2 gene mutations are much more common than TGFBR1 mutations; (2) TGFBR2 mutations are clustered in the C-lobe of the T?R-II kinase; and (3) many of the TGFBR2 mutated in human cancers coincide with those involved in Marfan-like syndromes as well as with the TGFBR2 orthologue in D. melanogaster. Thus, converging experimental evidence from these three very different sources strongly supports the hypothesis that TGF? receptor gene mutations can confer an aberrant activated cellular phenotype. Our specific aims are: 1. To predict the effects of TGFBR2 gene mutations on interactions with other proteins using structural biology approaches; 2. To determine which TGFBR2 gene mutations confer gain-of- function phenotypes using genetic assays in D. melanogaster; 3. To determine the effects of TGFBR2 gene mutations on TGF? signaling in mammalian cells; 4. To utilize selective chemical T?R kinase inhibitors to determine their potential therapeutic effects on gain-of-function TGFBR2 mutant cells. These studies are particularly important because TGF? antagonists are in (pre)clinical development for the treatment of (metastatic) cancer as well as fibrotic disorders. Thus, not only will our studies provide a precise understanding of the molecular pathobiology of disease-causing TGFBR mutations, but they will also inform the clinical development of TGF? pathway inhibitors for cancer and other disorders.