宫颈癌是女性常见恶性肿瘤。现有治疗方法对晚期或复发的宫颈癌疗效有限，需开拓宫颈癌的靶向治疗。理解宫颈癌中关键致癌基因活化机制并鉴定出它们的临床病理特征是开拓宫颈癌靶向治疗的前提。我们研究发现MAPk通路基因突变的宫颈癌患者预后差。MAPK1作为该通路的效应分子，在细胞增殖和凋亡中发挥重要作用。2014年nature中首次报导了宫颈鳞癌中存在MAPK1突变。该基因突变可能是部分宫颈癌的“驱动突变”，但它的致癌机制缺少研究。此外，该基因突变可能引起肿瘤对MAPK通路抑制剂产生耐药。我们已证实中国宫颈癌患者也存在该基因的热点突变，突变体导入NIH 3T3细胞后观察到致癌活性。因此，本项目将深入研究MAPK1突变在宫颈癌中的致癌机制；研究该突变对靶向药物的影响，筛选对突变体有效的抗肿瘤药；并且确定宫颈癌中MAPK1抑制剂治疗潜在的受益人群。该研究结果将促进相关靶向药物治疗宫颈癌临床试验的开展。

Worldwide, cervical cancer is the third most common cancer in women. Conventional treatment modalities cannot improve the survival of patients with recurrent or advanced diseases. Targeted therapy is desperately needed for cervical cancer. Detailed understanding of genomic abnormalities that drive subsets of cancer and identifying the associated clinicopathological characteristics are crucial for the development of targeted therapy. The MAPK pathway genes mutations were found to associate significantly with poorer relapse-free survival in our previous study. MAPK1, as downstream effector molecule of MAPK pathway, plays a pivotal role in cellular growth, proliferation and apoptosis. MAPK1 mutation in cervical cancer was firstly reported in Nature in 2014. Mutant MAPK1 may function as a “driver” in carcinogenesis of cervical cancer. However, its carcinogenic mechanism is not well understood. Furthermore, MAPK1 mutations may confer resistance to MAPK pathway inhibitors in targeted therapy. We previously testified that Chinese patients with cervical cancer harbored MAPK1 E322K mutations too, and we observed malignant transforming activity of the mutant. Here we will explore the carcinogenic mechanism of mutant MAPK1 in cervical cancer, screen out effective inhibitors for MAPK1-mutant tumors, and attempt to determine the frequency and clinicopathological characteristics of this mutation in a cohort of 820 Chinese patients with resected cervical cancers. Current study will significantly improve current cervical cancer treatment strategies for patients possessing MAPK1 mutation.