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Kinase activities in pancreatic ductal adenocarcinoma with prognostic and therapeutic avenues

Authors :
Andrea Vallés‐Martí
Richard R. deGoeij‐de Haas
Alex A. Henneman
Sander R. Piersma
Thang V. Pham
Jaco C. Knol
Joanne Verheij
Frederike Dijk
Hans Halfwerk
Elisa Giovannetti
Connie R. Jiménez
Maarten F. Bijlsma
Source :
Molecular Oncology, Vol 18, Iss 8, Pp 2020-2041 (2024)
Publication Year :
2024
Publisher :
Wiley, 2024.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a limited number of known driver mutations but considerable cancer cell heterogeneity. Phosphoproteomics provides a direct read‐out of aberrant signaling and the resultant clinically relevant phenotype. Mass spectrometry (MS)‐based proteomics and phosphoproteomics were applied to 42 PDAC tumors. Data encompassed over 19 936 phosphoserine or phosphothreonine (pS/T; in 5412 phosphoproteins) and 1208 phosphotyrosine (pY; in 501 phosphoproteins) sites and a total of 3756 proteins. Proteome data identified three distinct subtypes with tumor intrinsic and stromal features. Subsequently, three phospho‐subtypes were apparent: two tumor intrinsic (Phos1/2) and one stromal (Phos3), resembling known PDAC molecular subtypes. Kinase activity was analyzed by the Integrative iNferred Kinase Activity (INKA) scoring. Phospho‐subtypes displayed differential phosphorylation signals and kinase activity, such as FGR and GSK3 activation in Phos1, SRC kinase family and EPHA2 in Phos2, and EGFR, INSR, MET, ABL1, HIPK1, JAK, and PRKCD in Phos3. Kinase activity analysis of an external PDAC cohort supported our findings and underscored the importance of PI3K/AKT and ERK pathways, among others. Interestingly, unfavorable patient prognosis correlated with higher RTK, PAK2, STK10, and CDK7 activity and high proliferation, whereas long survival was associated with MYLK and PTK6 activity, which was previously unknown. Subtype‐associated activity profiles can guide therapeutic combination approaches in tumor and stroma‐enriched tissues, and emphasize the critical role of parallel signaling pathways. In addition, kinase activity profiling identifies potential disease markers with prognostic significance.

Details

Language :
English
ISSN :
18780261 and 15747891
Volume :
18
Issue :
8
Database :
Directory of Open Access Journals
Journal :
Molecular Oncology
Publication Type :
Academic Journal
Accession number :
edsdoj.8ff82023c7546bf9b7c1d4e26f666f5
Document Type :
article
Full Text :
https://doi.org/10.1002/1878-0261.13625