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

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

doi:10.1016/j.molcel.2021.07.021

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. Epub 2021 Aug 9.

Authors

Zhiwei Liu¹, Yingluo Liu¹, Lili Qian², Shangwen Jiang², Xiameng Gai³, Shu Ye⁴, Yuehong Chen², Xiaomin Wang², Linhui Zhai⁵, Jun Xu², Congying Pu¹, Jing Li⁶, Fuchu He⁷, Min Huang⁸, Minjia Tan⁹

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.

MeSH terms

Animals
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Cell Line, Tumor
Databases, Genetic
Drug Synergism
Enzyme Inhibitors / pharmacology*
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Guanine Nucleotide Exchange Factors / genetics
Guanine Nucleotide Exchange Factors / metabolism
Histone-Lysine N-Methyltransferase / antagonists & inhibitors
Histone-Lysine N-Methyltransferase / metabolism
Humans
Mass Spectrometry
Mice
Mice, Inbred BALB C
Mice, Nude
Mitogen-Activated Protein Kinases / metabolism
Molecular Targeted Therapy
Mutation*
Neoplasms / drug therapy*
Neoplasms / genetics
Neoplasms / metabolism
Neoplasms / pathology
Phosphoproteins / genetics
Phosphoproteins / metabolism*
Protein Tyrosine Phosphatase, Non-Receptor Type 11 / antagonists & inhibitors
Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism
Proteome*
Proteomics*
Proto-Oncogene Proteins p21(ras) / genetics*
Signal Transduction
Transcriptome
Xenograft Model Antitumor Assays

Substances

Enzyme Inhibitors
Guanine Nucleotide Exchange Factors
KRAS protein, human
PREX1 protein, human
Phosphoproteins
Proteome
DOT1L protein, human
Histone-Lysine N-Methyltransferase
Mitogen-Activated Protein Kinases
PTPN11 protein, human
Protein Tyrosine Phosphatase, Non-Receptor Type 11
Proto-Oncogene Proteins p21(ras)