Sos1变构位点作为Kras介导的血液恶性肿瘤治疗靶点的研究

Kras突变与青少年粒单核细胞白血病（JMML）的疾病进展加快密切相关,虽然目前已经有靶向Ras下游信号通路的临床药物，但普遍单药耐药性强或效果较弱，因此，寻找新的靶向策略具有重要意义。Sos1是重要的鸟嘌呤核苷酸交换因子，通过催化位点结合并激活Ras。Sos1晶体结构预示其变构位点能够特异性地结合激活型Ras-GTP，而不能结合Ras-GDP。我们前期研究发现在小鼠中敲除Sos1能够消除癌基因Kras对ERK信号通路的激活，延长小鼠寿命。因此，我们推测Sos1的变构位点是癌基因Kras诱导JMML的潜在治疗靶点。本研究将利用Sos1变构位点抑制剂及突变小鼠，明确Sos1变构位点在癌基因Kras诱导JMML中的作用；通过骨髓移植、人源化小鼠模型等，阐述其作用机制；同时，进一步探讨联合抑制Sos1变构位点和MEK对JMML的治疗效果，为靶向治疗JMML提供新的理论依据和靶点。

Clinical data showed that Kras mutations associate with accelerated disease progression or poor prognosis in several pediatric leukemias， for example, juvenile myelomonocytic leukemia (JMML). While strategies targeting Ras signaling downstream components have yielded clinical grade drugs, these drugs are considerable toxicity or less responsive. Therefore, looking for new targeting strategies has important research and clinical significance. Sos1 is an important guanine nucleotide exchange factor that binds and activates Ras through catalytic sites. Previously, we found that Sos1 knockout can inhibit the activation of downstream ERK signaling pathway mediated by oncogene Kras, and significantly prolong the life span of mice. Meanwihle, the crystal structure of Sos1 indicates that its allosteric site can specifically bind to the oncogene Ras-GTP, but not to the wild-type ras-GDP. So, we hypothesize that allosteric site of Sos1 is a potential therapeutic target of JMML induced by oncogenic Kras. This project will introduce allosteric site inhibitor and mutant mice of Sos1 to clarify the role of allosteric site of Sos1 in oncogenic Kras induced JMML. Further, we will study the mechanism of allosteric site of Sos1 in the occurrence and development of JMML by bone marrow transplantation, flow cytometry and human like mouse model. At the same time, this project will use small molecule inhibitor of Sos1 allosteric site and trametinib, an inhibitor of MEK signaling pathway, to test the effect of combination therapy at the cellular and mouse model levels.