Institute of Basic Medical Science, Wound Healing and Cell Biology Laboratory, Chinese PLA General Hospital, 100039 Beijing, China.
Department of Anesthesia, Dongzhimen Hospital, Beijing University of Chinese Medicine, 100700 Beijing, China.
Curr Top Med Chem. 2019;19(23):2176-2186. doi: 10.2174/1568026619666190828160804.
Pancreatic cancer is a highly malignant tumor with a 5-year survival rate of less than 6%, and incidence increasing year by year globally. Pancreatic cancer has a poor prognosis and a high recurrence rate, almost the same as the death rate. However, the available effective prevention and treatment measures for pancreatic cancer are still limited. The genome variation is one of the main reasons for the development of pancreatic cancer. In recent years, with the development of gene sequencing technology, in-depth research on pancreatic cancer gene mutation presents that a growing number of genetic mutations are confirmed to be in a close relationship with invasion and metastasis of pancreatic cancer. Among them, KRAS mutation is a special one. Therefore, it is particularly important to understand the mechanism of the KRAS mutation in the occurrence and development of pancreatic cancer, and to explore the method of its transformation into clinical tumor molecular targeted treatment sites, to further improve the therapeutic effect on pancreatic cancer. Therefore, to better design chemical drugs, this review based on the biological functions of KRAS, summarized the types of KRAS mutations and their relationship with pancreatic cancer and included the downstream signaling pathway Raf-MEK-ERK, PI3K-AKT, RalGDS-Ral of KRAS and the current medicinal treatment methods for KRAS mutations. Moreover, drug screening and clinical treatment for KRAS mutated cell and animal models of pancreatic cancer are also reviewed along with the prospect of targeted medicinal chemistry therapy for precision treatment of pancreatic cancer in the future.
胰腺癌是一种高度恶性肿瘤,5 年生存率低于 6%,全球发病率逐年上升。胰腺癌预后差,复发率高,几乎与死亡率相当。然而,目前用于胰腺癌的有效预防和治疗措施仍然有限。基因组变异是胰腺癌发展的主要原因之一。近年来,随着基因测序技术的发展,对胰腺癌基因突变的深入研究表明,越来越多的遗传突变被证实与胰腺癌的侵袭和转移密切相关。其中,KRAS 突变是一个特殊的例子。因此,了解 KRAS 突变在胰腺癌发生发展中的机制,探索其转化为临床肿瘤分子靶向治疗靶点的方法,对于进一步提高胰腺癌的治疗效果尤为重要。因此,为了更好地设计化学药物,本综述基于 KRAS 的生物学功能,总结了 KRAS 突变的类型及其与胰腺癌的关系,包括 KRAS 的下游信号通路 Raf-MEK-ERK、PI3K-AKT、RalGDS-Ral,以及目前针对 KRAS 突变的药物治疗方法。此外,还对 KRAS 突变的胰腺癌细胞和动物模型的药物筛选和临床治疗进行了综述,并展望了未来针对胰腺癌精准治疗的靶向药物化学治疗的前景。