胰腺导管腺癌 (pancreatic ductal adenocarcinoma, PDAC)是一种恶性程度很高，诊断和治疗都很困难的消化道恶性肿瘤，目前也没有有效的靶向PDAC的治疗。研究表明K-Ras原癌基因突变导致95%以上的侵袭性PDAC发生，但是，具体机制尚未清楚。基于已报道的实验和临床数据，我们先前提出PI3Kα/钙调蛋白(calmodulin, CaM)组合调控K-Ras4B，形成K-Ras4B/PI3Kα/CaM的三元复合物，诱导PDAC的发生。本项目拟在此科学假说的前提下，通过结构生物学、化学生物学、计算生物学和生物信息学等方法，揭示精确的K-Ras4B/PI3Kα/CaM三元复合物结构模型以及阐明PI3Kα/CaM协调调控K-Ras4B，诱导PDAC发生的机制。这些研究为三元复合物作为PDAC的药物靶标提供理论依据，也为PDAC的靶向治疗提供新的解决方案。

As one of particularly deadly type of digestive malignant tumors, the diagnosis and treatment of pancreatic ductal adenocarcinoma (PDAC) becomes difficult. Currently, there is no effective therapy to treat PDAC. It is well-documented that mutation of K-Ras proto-oncogene has associated with more than 95% invasive PDAC. However, the detailed mechanism remains unclear. Based on the available experimental and clinical data, we have previously proposed that K-Ras4B is regulated by both PI3Kα and calmodulin (CaM), generating a K-Ras4B/PI3Kα/CaM trimer, which is a key player in the formation of PDAC. Here, based on this hypothesis, we use structural biology, chemical biology, computational biology and bioinformatics to obtain the precise structure of K-Ras4B/PI3Kα/CaM trimer complex and uncover the role of K-Ras4B/PI3Kα/CaM trimer in the regulation of the formation of PDAC. This study will lay the foundation for the complex of K-Ras4B/PI3Kα/CaM trimer as a new target of K-Ras4B-driven PDAC and provide a new, promising therapeutic strategy to PDAC targeted therapy.