Dataset Information

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

ABSTRACT: KRAS mutant cancers, which feature the activation of multiple phosphorylation signaling pathways, remain a major challenge for cancer therapy. This study provides a landscape of the proteomics and phosphoproteomics of KRAS mutant cancers by analyzing different KRAS mutant human cancer cell lines across different tissues types. By integrating multi-omics analysis, we identify different robust subsets, which recapitulate the histological, pathological and prognostic features of human cancers.

ORGANISM(S): Homo Sapiens

SUBMITTER: Minjia Tan

PROVIDER: PXD026892 | iProX | Wed Jun 23 00:00:00 BST 2021

REPOSITORIES: iProX

ACCESS DATA

Publications

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

Liu Zhiwei Z Liu Yingluo Y Qian Lili L Jiang Shangwen S Gai Xiameng X Ye Shu S Chen Yuehong Y Wang Xiaomin X Zhai Linhui L Xu Jun J Pu Congying C Li Jing J He Fuchu F Huang Min M Tan Minjia M

Molecular cell 20210809 19

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 biologica ...[more]

PMID: 34375582

Similar Datasets

Project description:Mutant KRAS (mut-KRAS) is present in 30% of all human cancers and plays a critical role in cancer cell growth and resistance to therapy. There is evidence from colon cancer that mut-KRAS is a poor prognostic factor and negative predictor of patient response to molecularly targeted therapy. However, evidence for such a relationship in non small cell lung cancer (NSCLC) is conflicting. KRAS mutations are primarily found at codons 12 and 13, where different base changes lead to alternate amino acid substitutions that lock the protein in an active state. The patterns of mut-KRas amino acid substitutions in colon cancer and NSCLC are quite different, with aspartate (D) predominating in colon cancer (50%) and cysteine (C) in NSCLC (47%). Through an analysis of a recently completed biopsy biomarker-driven, molecularly targeted multi-arm trial of 215 evaluable patients with refractory NSCLC we show that mut-KRas-G12C/V but not total mut-KRAS predicts progression free survival for the overall group, and for the sorafenib and vandetanib treatment arms. Transcriptome microarray data shows differential expression of cell cycle genes between mut-KRas-G12C/V and G12D patient tumors. A panel of NSCLC cell lines with known mut-KRas amino acid substitutions was used to identify pathways activated by the different mut-KRas, showing that mut-KRas-G12D activates both PI-3-K and MEK signaling, while mut-KRas G12C does not, and alternatively activates RAL signaling. This finding was confirmed using immortalized human bronchial epithelial cells stably transfected with wt-KRAS and different forms of mut-KRAS. Molecular modeling studies show that the different conformation imposed by mut-KRas-G12C could lead to altered association with downstream signaling transducers compared to wild type and mut-KRas-G12D. The significance of the findings for developing mut-KRAS therapies is profound, since it suggests that not all mut-KRas amino acid substitutions signal to effectors in a similar way, and may require different therapeutic interventions. Gene expression profiles were measured in 22 core biopsies from patients with refractory non-small cell lung cancer included in the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE). All tumors were KRAS mutants, but with different patterns of amino acid substitutions. Supervised analysis of transcriptome profiling was performed to compare cysteine or valine KRAS mutants with other KRAS mutants.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets