PI3 Kinase调控c-Kit突变的自活化及其致癌能力的研究

Gain-of-function mutations of the receptor tyrosine kinase c-Kit have been identified in most gastrointestinal stromal tumor, mastocytosis and some core binding factor acute myeloid leukemia and melanoma. Unlike wild-type c-Kit, gain-of-function mutations of c-Kit are constitutively active without ligand stimulation, which is considered as the cause of cell transformation induced by c-Kit mutants. Inhibitors of c-Kit have been approved for clinic use in the treatment of malignancies that carry c-Kit mutations. However, some primary mutations and secondary mutations of c-Kit are resistant to the currently approved c-Kit inhibitors leading to treatment failure. In order for better drug design and to find more treatment targets, it is necessary to further study the activation mechanism of c-Kit mutants and elucidate how these c-Kit mutants induce cancer. In our previous studies, we found that PI3 kinase plays a crucial role in the ligand-independent activation of c-Kit mutants, and which is not dependent on the lipid kinase activity of PI3 kinase (Oncogene, 2014. 33(46): 5360-9; Cell Mol Life Sci, 2015. 72(22):4399-407), indicating that the non-kinase activity of PI3 kinase could be a good treatment target of malignancies carrying c-Kit mutations. In this study, we aim to further elucidate the mechanism that PI3 kinase regulates the ligand-independent activation of c-Kit mutants and cell transformation mediated by c-Kit mutants.

酪氨酸激酶受体c-Kit突变是绝大部分胃肠道间质瘤、肥大细胞增多症以及部分急性髓系白血病、黑色素瘤等恶性疾病的致病原因。数种c-Kit抑制剂已经用于上述疾病的靶向治疗，但部分原发性c-Kit突变以及靶向治疗后复发瘤产生的c-Kit二次突变对目前临床上应用的靶向治疗药物具有抗药性。我们在以前的研究中发现PI3 kinase在c-Kit突变的自活化中起关键作用，而且该作用不依赖于PI3 kinase的激酶活性（Oncogene, 2014. 33(46): 5360-9; Cell Mol Life Sci, 2015. 72(22):4399-407），PI3 kinase的非激酶活性有可能成为携带c-Kit突变的癌症靶向治疗的靶点。在本研究中，我们将进一步阐明PI3 kinase调控c-Kit突变活化和致癌机理，以及研究其成为治疗靶点的可能性。

酪氨酸激酶受体c-Kit突变是胃肠道间质瘤和肥大细胞增多症的主要致病性基因突变。目前，已有数种c-Kit抑制剂用于上述疾病的靶向治疗，但部分原发性c-Kit突变以及靶向治疗后复发瘤产生的c-Kit二次突变对目前临床上应用的靶向治疗药物具有抗药性。我们在以前的研究中发现PI3 kinase在c-Kit突变的自活化中起关键作用。在本课题中，我们研究了PI3 kinase各亚型对c-Kit突变自活化的作用；PI3 kinase亚型对c-Kit下游信号传递的作用；PI3 kinase亚型对c-Kit突变引起的细胞癌变的作用；PI3 kinase各亚型在c-Kit突变抗药性中的作用，以进一步阐明PI3 kinase调控c-Kit突变活化和致癌机理，以及研究其成为治疗靶点的可能性。.通过在c-Kit基因中引入各种突变，并应用细胞系和试验动物，我们发现PI3 kinase各亚型在不同KIT表达细胞的信号传递中起的作用不尽相同；发现对c-Kit突变自活化起关键作用的PI3 kinase亚型p110δ；发现PI3 kinase与KIT的结合在耐药性胃肠道间质瘤携带的KIT二次突变的活化和下游信号传递中起至关重要的作用，并影响肿瘤的形成以及对靶向治疗药物的反应性。.这些结果在目前知识的基础上，进一步说明了PI3 Kinase在KIT突变引起的肿瘤中起重要作用，PI3 Kinase在KIT二次突变中的重要作用提示我们或许可以通过阻断PI3 Kinase与KIT结合的方法治疗耐药性胃肠道间质瘤，目前该类肿瘤的治疗目前在临床上还是一个难题，该方法给耐药性胃肠道间质瘤的治疗提供了一种新的可能。