MAPK1突变在宫颈癌中的致癌机制及临床意义

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.

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。

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。我们的前期研究结果显示PIK3CA、KRAS、HER2是宫颈癌中最常见的驱动突变，这些基因突变正在成为恶性肿瘤治疗中的非常有前景的小分子抑制剂治疗靶点。我们采用直接测序的方法检测了大样本浸润性宫颈癌病例中HER2， KRAS ， PIK3CA 和MAPK1的体系突变情况， 在体外实验中研究E322K突变的MAPK1基因对宫颈癌发生的影响，研究PIK3CA E542K 和 E545K突变对宫颈癌细胞糖酵解和增殖的影响并探索其潜在机制。宫颈癌样品中 HER2， KRAS 和 PIK3CA 体系突变发生率分别是 3.15%, 3.25% 和 14.38%。HER2 中最常见突变是S310F, KRAS 中最常见的突变是G12D和G13D, PIK3CA最常见的突变是E545K和E542K。HER2或KRAS在非鳞癌肿瘤中的突变率显著地比鳞癌高。携带PIK3CA突变的患者预后最好，其次是三个基因均为野生型的患者，再次是HER2突变的患者，而携带KRAS 突变的患者预后最差。MAPK1突变在鳞癌中发生率为2.91%。 85%的突变体为E322K。相当一部分携带MAPK1突变的宫颈癌伴有酪氨酸激酶受体通路其他基因的突变。体外实验证实gMAPK1+MAPK1mut细胞增殖比gMAPK1+MAPK1wt 快。我们的研究为酪氨酸激酶抑制剂， MTOR抑制剂和MAPK通路抑制剂在宫颈癌中开展个体化治疗的临床试验提供了依据治疗宫颈癌的临床试验时应考虑到一部分患者合并PIK3CA或KRAS突变。MAPK1 E322K为宫颈鳞癌的热点突变，通过体外细胞。宫颈癌中HER2、KRAS和PIK3CA突变有各自鲜明的临床病理预后特征。在开展HER2或 MAPK通路抑制剂临床试验时应该优先入组宫颈非鳞状细胞癌亚型的患者。设计HER2-TKIs的实验证明MAPK1 E322K突变是有功能的激活突变。携带了PI3KCA E542K 或 E545K突变的宫颈癌通过PIK3CA/β-catenin/SIRT3 信号通路促进糖代谢和增殖,这将为宫颈癌治疗提供新的靶点。