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  3. A proteomic and phosphoproteomic landscape of KRAS mutant cancers identifies combination therapies

A proteomic and phosphoproteomic landscape of KRAS mutant cancers identifies combination therapies

  • Mol Cell. 2021 Oct 7;81(19):4076-4090.e8. doi: 10.1016/j.molcel.2021.07.021.
Zhiwei Liu 1,  Yingluo Liu 1,  Lili Qian 2,  Shangwen Jiang 2,  Xiameng Gai 3,  Shu Ye 4,  Yuehong Chen 2,  Xiaomin Wang 2,  Linhui Zhai 5,  Jun Xu 2,  Congying Pu 1,  Jing Li 6,  Fuchu He 7,  Min Huang 8,  Minjia Tan 9
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 3 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.
  • 4 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • 5 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China; Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang, China.
  • 6 Department of Bioinformatics and Biostatistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
  • 7 State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China.
  • 8 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China. Electronic address: mhuang@simm.ac.cn.
  • 9 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China. Electronic address: mjtan@simm.ac.cn.
PMID: 34375582 DOI: 10.1016/j.molcel.2021.07.021
Abstract

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.

Keywords

DOT1L; KRAS mutation; SHP2; cancer; drug sensitivity; heterogeneity; phosphoproteomics; proteomics; subtype; therapy.

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