Dataset Information

Phospho-proteomics enables classification of cancer subtypes and nomination of druggable kinases for individual patients of diffuse-type gastric cancer

ABSTRACT: The diffuse-type gastric cancer (DGC) constitutes a subgroup of gastric cancer with poor prognosis and no effective molecular therapies. Here, we report a phosphoproteomic landscape of DGC derived from 83 tumors together with their nearby tissues. Based on phosphorylation, DGC could be classified into three molecular subtypes with distinct overall survival (OS) and chemosensitivity. We identified 16 kinases whose activities were associated with poor OS. These activated kinases covered several cancer hallmark pathways, with the MTOR signaling network being the most frequently activated. We proposed a patient-specific strategy based on the hierarchy of clinically actionable kinases for prioritization of kinases for further clinical evaluation. Our global data analysis indicates that in addition to finding activated kinase pathways in DGC, large-scale phosphoproteomics could be used to classify DGCs into subtypes that are associated with distinct clinical outcomes as well as nomination of kinase targets that may be inhibited for cancer treatments.

ORGANISM(S): Homo Sapiens

SUBMITTER: Jun Qin

PROVIDER: PXD018293 | iProX | Tue Mar 31 00:00:00 BST 2020

REPOSITORIES: iProX

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Publications

Phosphoproteomics Enables Molecular Subtyping and Nomination of Kinase Candidates for Individual Patients of Diffuse-Type Gastric Cancer.

Tong Mengsha M Yu Chunyu C Shi Jinwen J Huang Wenwen W Ge Sai S Liu Mingwei M Song Lei L Zhan Dongdong D Xia Xia X Liu Wanlin W Feng Jinwen J Shi Wenhao W Ji Jiafu J Gao Jing J Shi Tieliu T Zhu Weimin W Ding Chen C Wang Yi Y He Fuchu F Shen Lin L Li Tingting T Qin Jun J

iScience 20191106

The diffuse-type gastric cancer (DGC) constitutes a subgroup of gastric cancer with poor prognosis and no effective molecular therapies. Here, we report a phosphoproteomic landscape of DGC derived from 83 tumors together with their nearby tissues. Based on phosphorylation, DGC could be classified into three molecular subtypes with distinct overall survival (OS) and chemosensitivity. We identified 16 kinases whose activities were associated with poor OS. These activated kinases covered several ca ...[more]

PMID: 31751824

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Project description:Triple negative breast cancer (TNBC) is heterogeneous with patients exhibiting at least two molecular subtypes, basal-like (BL) and claudin-low (CL). MEK inhibitor (MEKi) treatment of BL and CL cell lines and mouse model tumors induced subtype-specific alterations in overall kinome activity referred to as protein kinase reprogramming. BL- and CL-specific reprogramming involving increases in receptor tyrosine kinases was also seen in TNBC patients comparing tumor samples before and after a one week treatment with the MEKi, trametinib. Combination of kinase inhibitors targeted to the BL and CL reprogrammed signatures would need to be individually selected due to the heterogeneous resiliency of BL and CL kinomes. To overcome this “reprogramming dilemma” we targeted the transcriptional co-activator BRD4 with BET bromodomain inhibitors, JQI and IBET151; both strongly inhibited kinome reprogramming and onset of MEKi resistance in BL and CL cells. Targeting chromatin modifiers may therapeutically block resistance due to kinome reprogramming.BL and CL TNBC are commonly treated as a single disease despite genomic studies showing they represent distinct molecular subtypes1. Recent Cancer Genome Atlas data demonstrated that the 518 protein kinases in the human genome (the kinome) were infrequently mutated in BL breast cancer; however, EGFR, KRAS and BRAF were amplified in 22, 32 and 31% of BL tumors, respectively. These findings are consistent with frequent activation of the BRAF-MEK-ERK pathway in TNBC2,3 and inhibitors targeting kinases in this pathway are currently in clinical trials for TNBC. As single agents, targeted kinase inhibitors generally fail to sustain durable responses when used to treat a range of human cancers including TNBC4-6. Onset of kinase inhibitor resistance can be due to selection of mutations in the targeted kinase7,8, activating mutations or amplification of RAS or downstream kinases9,10 or kinome reprogramming, a process in which there are system-wide changes in kinase networks11-13. Each of these resistance mechanisms allows the cancer cell to circumvent the targeted inhibition of specific kinases14. We previously developed chemical, proteomic methods that assay the activation state of protein kinases en masse15,16. Our methods utilize ¬Multiplexed Inhibitor Beads (MIBs), mixtures of covalently immobilized, linker adapted, kinase inhibitors. The immobilized inhibitors are primarily type I kinase inhibitors that preferentially bind activated (versus inactive) kinase17. Kinase capture is highly reproducible and is a function of kinase affinity for different immobilized inhibitors as well as the kinase activation state. Activated kinases preferentially bind, inactive kinases do not. By coupling MIB capture with mass spectrometry (MIB/MS), the technique allows quantitative interrogation of hundreds of kinases in a single mass spectrometry run. This also interrogates kinases known by sequence but which have been understudied due to lack of reagents such as specific phospho-antibodies. We report here both in preclinical models and patients that BL and CL TNBC have different baseline kinome activation states and both respond differently to MEKi with subtype-specific tyrosine kinase reprogramming. To avoid treatment strategy that uses multiple kinase inhibitors in individual patients, we discovered a novel pharmacologic strategy to block the initial reprogramming response to MEKi involving inhibition of epigenetic processes.

Dataset Information

Phospho-proteomics enables classification of cancer subtypes and nomination of druggable kinases for individual patients of diffuse-type gastric cancer

Publications

Phosphoproteomics Enables Molecular Subtyping and Nomination of Kinase Candidates for Individual Patients of Diffuse-Type Gastric Cancer.

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