The mechanisms driving brain oncogenesis by FGFR-TACC gene fusions

描述（由申请人提供）：癌症成功靶向治疗的历史在很大程度上与血液恶性肿瘤和最近某些类型上皮癌中复发性和致癌基因融合的失活一致。多形性胶质母细胞瘤（GBM）是人类癌症中最致命和最不可治愈的形式之一，针对GBM中常见遗传变异的靶向治疗并没有改变该疾病令人沮丧的临床结果。我们最近鉴定了FGFR-TACC基因融合体作为GBM中高度致癌性和复发性基因融合体的第一个例子，靶向它们在特定肿瘤亚型中的依赖性，并观察到显著的抗肿瘤作用。这条研究路线最近已经成熟到临床试验。最近在几种其他肿瘤类型中鉴定了相同的基因融合，从而将FGFR-TACC融合确定为人类癌症中最常见的染色体易位之一。从机制的角度来看，我们已经发现了FGFR-TACC融合体在有丝分裂期间触发染色体异常分离的意外能力，从而引发染色体不稳定性（CIN）和非整倍性，这是人类癌症的两个标志。然而，我们对FGFR-TACC融合体的致癌活性的全部谱以及FGFR-TACC融合体在人GBM中触发生长促进信号和非整倍性的程度仍然没有完全的理解。该提案的中心目标是破译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，通过一个组成型活性酪氨酸激酶（FGFR）在有丝分裂纺锤极的异常错误定位，破坏了正确的染色体分离有丝分裂，这种新的功能代表了一个关键的事件脑肿瘤的启动。FGF-TACC融合的这种主要活性可能与其他促进生长的信号传导功能合作，补充与有丝分裂保真度和非整倍性损失相关的细胞适应性降低，以诱导全面发展的肿瘤发生。为了确定FGFR-TACC融合引起的脑肿瘤起始和CIN的机制决定因素，该提议将追求三个具体目标。在第一个目标中，我们将鉴定由FGFR-TACC融合蛋白的异常激酶活性直接修饰的底物的酪氨酸磷酸化景观。在第二个目标中，我们将确定FGFR-TACC融合破坏正确染色体分离的机制。在第三个目的中，我们将在条件性敲入小鼠品系中对CIN、FGFR 3-TACC 3融合体的促生长信号传导功能和肿瘤起始能力进行建模，所述条件性敲入小鼠品系在所选细胞中表达FGFR 3-TACC 3蛋白。这一创新提案的预期总体影响是，它将从根本上推进我们对FGFR-TACC融合体的机制理解，并为优化人类癌症中FGFR-TACC基因融合体的发现所促成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.