PI3K/AKT通路激活常发生在KRAS突变型结直肠癌 (colorectal cancer, CRC)中。除PIK3CA突变外，AKT1突变亦可激活PI3K/AKT通路。申请者前期利用NGS分析634例中国CRC患者突变谱发现，AKT1常与KRAS G13D共突变，在晚期KRAS突变型CRC患者中，AKT1突变组预后显著好于PIK3CA突变组。本研究拟在前期基础上，应用比较研究方法，通过比较大样本KRAS突变型CRC中AKT1和PIK3CA突变患者临床病理特征及预后差异，确定AKT1突变在KRAS突变型CRC中的临床意义。通过比较AKT1与PIK3CA突变对KRAS突变型CRC细胞增殖、凋亡和侵袭转移的影响，阐明AKT1突变在KRAS突变型CRC中的作用。通过检测PI3K/AKT+MEK双重抑制剂对AKT1+KRAS共突变细胞的作用，探索AKT1+KRAS共突变CRC患者的靶向治疗策略。

PI3K/AKT pathway activation frequently occurs in concomitance with KRAS mutation in colorectal cancer (CRC), leading to poor prognosis. AKT1 mutations, same with PIK3CA mutations, can result in PI3K/AKT pathway activation. We previously detected the mutation profiling of 634 Chinese CRC patients by next-generation sequencing (NGS). The results showed that AKT1 mutations commonly coexisted with KRAS G13D mutations. We further found that AKT1 mutant patients with KRAS mutant metastatic CRC showed better overall survival as compared to PIK3CA mutant patients, suggesting that AKT1 and PIK3CA mutations may be not functionally equivalent in KRAS mutant CRC. However, the role of AKT1 mutation in KRAS mutant CRC remains elusive. In this work, in comparison with PIK3CA mutations, the clinicopathologic and molecular features of AKT1 mutations in a large cohort of KRAS mutant CRC patients are described. The role of AKT1 mutation in KRAS mutant CRC cell growth, apoptosis, invasion and metastasis is detected in vitro and in vivo, as compared to PIK3CA mutation. Moreover, the effects of PI3K/AKT and MEK inhibitor combinations on AKT1+KRAS mutant CRC cells are investigated. Our study aims to identify the role and clinical significance of AKT1 mutations in KRAS mutant CRC, and to explore the targeted intervention of AKT1 mutations in KRAS mutant CRC.