The mechanisms driving brain oncogenesis by FGFR-TACC gene fusions

描述(申请人提供)：癌症靶向治疗的成功历史在很大程度上与血液系统恶性肿瘤和最近在某些类型的上皮性癌症中复发和致癌基因融合失活的情况一致。多形性胶质母细胞瘤(GBM)是人类最致命、最无法治愈的癌症之一，针对GBM常见基因改变的靶向治疗并未改变该病令人沮丧的临床结果。我们最近已经确定FGFR-TACC基因融合是第一个在GBM中高度致癌和复发的基因融合的例子，针对它们在特定的肿瘤亚型中的依赖性，并观察到显著的抗肿瘤效果。这条研究路线最近已经成熟，准备进行临床试验。最近在其他几种肿瘤类型中发现了相同的基因融合，从而确立了FGFR-TACC融合是人类癌症中最常见的染色体易位之一。从机制的角度，我们发现了FGFR-TACC融合在有丝分裂过程中意外地触发了染色体的异常分离，从而引发了染色体不稳定(CIN)和非整倍体，这是人类癌症的两个特征。然而，我们仍然不完全了解FGFR-TACC融合的全部致癌活性，以及人GBM中FGFR-TACC融合在多大程度上触发了促进生长的信号和非整倍体。这项提议的中心目标是破译FGFR-TACC融合蛋白如何机械地促进恶性转化。我们的中心假设是，FGFR-TACC融合蛋白通过在有丝分裂纺锤体极上异常定位一个结构性活性酪氨酸激酶(FGFR)，破坏了有丝分裂中适当的染色体分离，并且这一新功能代表了脑瘤发生的关键事件。这种融合的主要活性很可能与其他促进生长的信号功能协同作用，以补充与有丝分裂保真度和非整倍体丧失相关的细胞适合性降低，以诱导全面的肿瘤发生。为了确定FGFR-TACC融合所引发的脑肿瘤发生和CIN的机制决定因素，该提案将追求三个具体目标。在第一个目标中，我们将鉴定直接由FGFR-TACC融合蛋白的异常激酶活性修饰的底物的酪氨酸磷酸化情况。在第二个目标中，我们将确定FGFR-TACC融合破坏适当的染色体分离的机制。在第三个目标中，我们将在一个在选定细胞中表达FGFR3-TACC3蛋白的条件性敲入鼠品系中模拟FGFR3-TACC3融合的CIN、促生长信号功能和肿瘤启动能力。这一创新建议的预期总体影响是，它将从根本上促进我们对FGFR-TACC融合的机制理解，并为优化因发现人类癌症中的FGFR-TACC基因融合而产生的新治疗策略奠定基础。

DESCRIPTION (provided by applicant): The history of successful targeted therapy of cancer largely coincides with the inactivation of recurrent and oncogenic gene fusions in hematological malignancies and recently in some types of epithelial cancer. Glioblastoma multiforme (GBM) is among the most lethal and incurable forms of human cancer and targeted therapies against common genetic alterations in GBM have not changed the dismal clinical outcome of the disease. We have recently identified FGFR-TACC gene fusions as the first example of highly oncogenic and recurrent gene fusions in GBM, targeted their dependency in a particular tumor subtype, and observed dramatic anti-tumor effects. This line of investigation has recently matured towards a clinical trial. The same gene fusions have recently been identified in several other tumor types, thus establishing FGFR-TACC fusions as one of the most frequent chromosomal translocations in human cancer. From a mechanistic standpoint, we have discovered the unexpected capacity of FGFR-TACC fusions to trigger aberrant segregation of chromosomes during mitosis, thus initiating chromosomal instability (CIN) and aneuploidy, two hallmarks of human cancer. However, we still have incomplete understanding of the full repertoire of the oncogenic activities of FGFR-TACC fusions and the extent to which FGFR-TACC fusions in human GBM trigger growth-promoting signals and aneuploidy. The central objective of this proposal is to decipher how mechanistically FGFR-TACC fusion proteins promote malignant transformation. Our central hypothesis is that the FGFR-TACC fusion protein, through an aberrant mislocalization of a constitutively active tyrosine kinase (FGFR) over the mitotic spindle pole, disrupts proper chromosome segregation in mitosis and that this novel function represents a critical event for brain tumor initiation. This primary activity of FGF-TACC fusions is likely to cooperate with other growth-promoting signaling functions that complement the reduced cellular fitness associated with loss of mitotic fidelity and aneuploidy, to induce full-blown-tumorigenesis. To identify the mechanistic determinants of brain tumor initiation and CIN instigated by FGFR-TACC fusions, this proposal will pursue three specific aims. In the first aim, we will identify the tyrosine phosphorylation landscape of substrates directly modified by the aberrant kinase activity of FGFR- TACC fusion proteins. In the second aim, we will determine the mechanism by which FGFR-TACC fusions disrupt proper chromosome segregation. In the third aim, we will model the CIN, growth promoting signaling functions and tumor initiating capacity of the FGFR3-TACC3 fusion in a conditional knock-in mouse strain that ex- presses the FGFR3-TACC3 protein in selected cells. The expected overall impact of this innovative proposal is that it will fundamentally advance our mechanistic understanding of FGFR-TACC fusions and lay the foundation for the optimization of the new therapeutic strategies that have been precipitated by the discovery of FGFR-TACC gene fusions in human cancer.