癌症研究
细胞生物学
信号转导
激酶
磷酸化
MAPK/ERK通路
突变
合成致死
神经母细胞瘤RAS病毒癌基因同源物
癌细胞
作者
Zhiwei Liu,Yingluo Liu,Lili Qian,Shangwen Jiang,Xiameng Gai,Shu Ye,Yuehong Chen,Xiaomin Wang,Linhui Zhai,Jun Xu,Congying Pu,Jing Li,Fuchu He,Min Huang,Minjia Tan
标识
DOI:10.1016/j.molcel.2021.07.021
摘要
KRAS mutant cancer, characterized by the activation of a plethora of phosphorylation signaling pathways, remains a major challenge for cancer therapy. Despite recent advancements, a comprehensive profile of the proteome and phosphoproteome is lacking. This study provides a proteomic and phosphoproteomic landscape of 43 KRAS mutant cancer cell lines across different tissue origins. By integrating transcriptomics, proteomics, and phosphoproteomics, we identify three subsets with distinct biological, clinical, and therapeutic characteristics. The integrative analysis of phosphoproteome and drug sensitivity information facilitates the identification of a set of drug combinations with therapeutic potentials. Among them, we demonstrate that the combination of DOT1L and SHP2 inhibitors is an effective treatment specific for subset 2 of KRAS mutant cancers, corresponding to a set of TCGA clinical tumors with the poorest prognosis. Together, this study provides a resource to better understand KRAS mutant cancer heterogeneity and identify new therapeutic possibilities.
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