Biology of Imatinib-Resistant Mutants of BCR-ABL

描述（由申请人提供）： 大多数早期慢性粒细胞白血病（CML）患者对伊马替尼（BCR-ABL的特异性抑制剂，CML的酪氨酸激酶）的治疗达到持久的反应。然而，在晚期疾病患者中复发是频繁的，通常是BCR-ABL激酶结构域（KD）点突变的结果。ve患者，与突变体在没有伊马替尼的情况下相对于野生型BCR-ABL的生长优势一致。此外，BCR-ABL的ATP结合环的突变赋予不良预后，而不管它们对伊马替尼的敏感性如何。 这些观察结果表明，KD突变可能会改变CML的生物学，除了和独立的作用，赋予伊马替尼耐药。与此一致，我们有初步的数据表明，在一些突变体和野生型BCR-ABL之间的转化能力的差异，而这些差异可能与激酶活性的改变在某些情况下，我们有数据表明，KD突变也改变信号转导。我们建议全面分析一组从CML患者中分离的BCR-ABL突变体。我们将确定激酶活性的动力学参数，信号通路的激活（使用一种新的极其敏感的磷酸蛋白质组学方法）和基因表达谱，并将这些数据与生物测定中的转化效力相关联。我们将整合这些信息，以确定候选介质或多或少的侵略性表型，然后将在适当的生物系统中进行验证。这项研究有两个总体目标。首先，我们将阐明KD突变在CML疾病进展中的作用。由于对CML从慢性期进展到加速期和急变期的机制知之甚少，这将增加对CML生物学的了解。其次，我们将在严格控制的实验系统中确定显着影响转化效力的介质。使用这种方法，我们的目标是确定新的治疗靶点，可用于治疗CML，并进一步用于目前没有有效疗法的其他类型的癌症。 一些慢性粒细胞白血病患者在伊马替尼（格列卫）治疗后复发，因为他们在一个关键蛋白质中发生突变。有证据表明，这些突变中的一些也可能有助于白血病的进展，并赋予患者非常糟糕的预后。我们将精确地研究突变如何使白血病更具侵略性，目的是确定在介导更具侵略性行为中至关重要的蛋白质。这些关键蛋白质可以作为治疗慢性髓细胞白血病的药物靶点，并进一步用于其他类型的癌症。

DESCRIPTION (provided by applicant): Most patients with early chronic myeloid leukemia (CML) achieve durable responses to treatment with imatinib, a specific inhibitor of BCR-ABL, the tyrosine kinase responsible for CML. However, relapse is frequent in patients with advanced disease and usually is the result of point mutations in the kinase domain (KD) of BCR-ABL. Unexpectedly, KD mutant clones were also detected in imatinib-nave patients, consistent with a growth advantage of mutants over wild type BCR-ABL in the absence of imatinib. Moreover, mutations in the ATP-binding loop of BCR-ABL confer a poor prognosis irrespective of their sensitivity to imatinib. These observations suggest that KD mutations may alter the biology of the CML in addition to and independent of their role in conferring imatinib resistance. Consistent with this, we have preliminary data that show differences in transformation potency between some mutants and wild type BCR-ABL. While these differences may be related to altered kinase activity in some cases, we have data showing that KD mutations also alter signal transduction. We propose to comprehensively analyze a panel of BCR-ABL mutants isolated from CML patients. We will determine kinetic parameters of kinase activity, activation of signaling pathways (using a novel extremely sensitive phosphoproteomics approach) and gene expression profiles, and correlate these data with transformation potency in biological assays. We will integrate this information to identify candidate mediators of a more or less aggressive phenotype that will then be validated in the appropriate biological systems. This study has two global objectives. Firstly, we will clarify role of KD mutations for disease progression of CML. Given that the mechanisms responsible for progression of CML form the chronic phase to accelerated and blastic phase are poorly understood, this will increase the knowledge of CML biology. Secondly, we will identify mediators that significantly affect transformation potency in a tightly controlled experimental system. Using this approach, we aim to identify novel therapeutic targets that could be exploited for the treatment of CML, and further, for other types of cancer for which there are currently no effective therapies available. Some patients with chronic myeloid leukemia relapse on therapy with imatinib (Gleevec), because they develop mutations in a critical protein. There is evidence that some of these mutations may also contribute to leukemia progression and confer a very bad prognosis to patients. We will study precisely how the mutations make the leukemia more aggressive, with the aim of identifying proteins that are critical in mediating the more aggressive behavior. Such crucial proteins may then be exploited as drug targets for the treatment of chronic myeloid leukemia, and further, for other types of cancer.