Kinase Activities in Pancreatic Ductal Adenocarcinoma with Prognostic and Therapeutic Avenues DOI

Andrea Vallés Martí,

Richard Haas,

Alex A. Henneman

и другие.

Опубликована: Янв. 1, 2023

Background: Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with limited number of known driver mutations but considerable cancer cell heterogeneity. Phosphoproteomics provides direct read-out aberrant signalling and the resultant clinically relevant phenotype. Methods: Mass spectrometry (MS)-based proteomics phosphoproteomics were applied to 42 PDAC tumors. To this end, protein lysates subjected tryptic digestion sequential phosphopeptide capture using pY antibodies IMAC beads followed by nanoLC-MS/MS database searching. Functional data mining was performed Integrative iNferred Kinase Activity (INKA) scoring, ssGSEA PTM-SEA. subtypes investigated consensus clustering. The collected correlated genomic patient survival outcomes. Findings: Data encompassed over 19936 pS/T (in 5412 phosphoproteins) 1208 sites 501 total 3756 proteins. Proteome identified three distinct tumor intrinsic stromal features. Subsequently, phospho-subtypes apparent: two tumour-intrinsic (Phos1/2) one (Phos3), resembling molecular subtypes. Phos displayed differential phosphorylation signals kinase activity, such as FGR GSK3 activation in Phos1, SRC family EPHA2 Phos2, EGFR, INSR, MET, ABL1, HIPK1, JAK PRKCD Phos3. activity analysis an external cohort supported our findings underscored importance PI3K/AKT ERK pathways, among other. Interestingly, unfavorable prognosis higher RTK, MAPK CDK high proliferation, whereas long associated MYLK, ILK, PTK6 previously unknown. Interpretation: Subtype-associated profiles can guide therapeutic combination approaches tumour stroma enriched tissues, emphasize critical role parallel pathways. In addition, profiling identifies potential markers prognostic significance.Funding: This project Dutch Cancer Society (KWF Kankerbestrijding, grant KWF2016-1 / 10212 C.R.J., M.F.B. E.G.). Center Amsterdam Netherlands Organisation for Scientific Research (NWO-Middelgroot 91116017) are acknowledged support mass infrastructure Surfsara computing (reference e-infra180166).Declaration Interest: has received research funding from Celgene, Frame Therapeutics, Lead Pharma. He acted consultant Servier. Ethical Approval: Tumor tissue specimens, snap-frozen liquid nitrogen stored at -80°C, retrospectively archive Department Pathology (approved Committee Review Biobanks, CTB.2015-081) purpose phosphoproteomic research. Retrospective collection conducted accordance ethical guidelines UMC Code, based on 'Code conduct Health Research' (Dutch Regulation Research).

Язык: Английский

Gemcitabine and ATR inhibitors synergize to kill PDAC cells by blocking DNA damage response DOI Creative Commons
Stefanie Höfer, Larissa Frasch,

Sarah Brajkovic

и другие.

Molecular Systems Biology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 21, 2025

Язык: Английский

Процитировано

2
Simulations probe the role of space in the interplay between drug-sensitive and drug-resistant cancer cells DOI Creative Commons

Kira Pugh,

Rhys D.O. Jones, Gibin Powathil

и другие.

Journal of Theoretical Biology, Год журнала: 2025, Номер unknown, С. 112048 - 112048

Опубликована: Фев. 1, 2025

Язык: Английский

Процитировано

1
The pan-cancer proteome atlas, a mass spectrometry-based landscape for discovering tumor biology, biomarkers, and therapeutic targets DOI

Jaco C. Knol,

Mengge Lyu,

Franziska Böttger

и другие.

Cancer Cell, Год журнала: 2025, Номер unknown

Опубликована: Май 1, 2025

Язык: Английский

Процитировано

1
Exploring the Therapeutic Potential of Focal Adhesion Kinase Inhibition in Overcoming Chemoresistance in Pancreatic Ductal Adenocarcinoma DOI

Fabio Scianò,

Francesca Terrana,

Camilla Pecoraro

и другие.

Future Medicinal Chemistry, Год журнала: 2024, Номер 16(3), С. 271 - 289

Опубликована: Янв. 25, 2024

Pancreatic ductal adenocarcinoma (PDAC) is among the leading causes of cancer-related deaths worldwide. Focal adhesion kinase (FAK) a nonreceptor tyrosine often overexpressed in PDAC. FAK has been linked to cell migration, survival, proliferation, angiogenesis and adhesion. This review first highlights chemoresistant nature Second, role PDAC cancer progression resistance carefully described. Additionally, it discusses recent developments inhibitors as valuable drugs treatment PDAC, with focus on diamine-substituted-2,4-pyrimidine-based compounds, which represent most potent class clinical trials for disease. To conclude, relevant computational studies performed are reported highlight key structural features required interaction protein, aim optimizing this novel targeted therapy.

Язык: Английский

Процитировано

5
Poly-pharmacology of existing drugs: How to crack the code? DOI Creative Commons
Baptiste Mouysset, Marion Le Grand, Luc Camoin

и другие.

Cancer Letters, Год журнала: 2024, Номер 588, С. 216800 - 216800

Опубликована: Март 14, 2024

Drug development in oncology is highly challenging, with less than 5% success rate clinical trials. This alarming figure points out the need to study more details multiple biological effects of drugs specific contexts. Indeed, comprehensive assessment drug poly-pharmacology can provide insights into their therapeutic and adverse effects, optimize utilization maximize Recent technological advances have made possible in-depth investigation poly-pharmacology. review first highlights high-throughput methodologies that been used unveil new mechanisms action existing drugs. Then, we discuss how emerging chemo-proteomics strategies allow effectively dissecting an unsupervised manner.

Язык: Английский

Процитировано

5
The trend toward more target therapy in pancreatic ductal adenocarcinoma DOI Creative Commons
Chiara Deiana,

Margherita Agostini,

Giovanni Brandi

и другие.

Expert Review of Anticancer Therapy, Год журнала: 2024, Номер 24(7), С. 525 - 565

Опубликована: Май 20, 2024

Introduction Despite the considerable progress made in cancer treatment through development of target therapies, pancreatic ductal adenocarcinoma (PDAC) continues to exhibit resistance this category drugs. As a result, chemotherapy combination regimens remain primary approach for aggressive cancer.

Язык: Английский

Процитировано

5
Non-thermal plasma as promising anti-cancer therapy against bladder cancer by inducing DNA damage and cell cycle arrest DOI Creative Commons
Jojanneke Stoof,

Zakaria Kalmoua,

Ana Sobota

и другие.

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Янв. 17, 2025

Bladder cancer often recurs, necessitating innovative treatments to reduce recurrence. We investigated non-thermal plasma's potential as a novel anti-cancer therapy, focusing on plasma-activated solution (PAS), created by exposing saline plasma. Our study aims elucidate the biological effects of PAS bladder cell lines in vitro, well combination with mitomycin C (MMC), using clinically relevant settings. treatment exerts potent cytotoxic effect through production intracellular reactive oxygen species, resulting DNA damage and subsequent induction G1 cycle arrest/senescence. This is induced via upregulation checkpoint signalling repair pathways LC-M/MS-based phospho-proteomics. Importantly, combining MMC reveals synergistic (Combination Index 0.59-0.67), suggesting utilizing therapies. findings demonstrate PAS's mode action suggest its promising for cancer, warranting further clinical studies.

Язык: Английский

Процитировано

0
Celebrating Ulrik Ringborg: Multi-Omics-Based Patient Stratification for Precision Cancer Treatment DOI Creative Commons
Maria‐Veronica Teleanu, Annika Schneider, Claudia R. Ball

и другие.

Biomolecules, Год журнала: 2025, Номер 15(5), С. 693 - 693

Опубликована: Май 10, 2025

Precision oncology is becoming a mainstay in the standard of care for cancer patients. Recent technological advancements have significantly lowered cost various tumor profiling approaches, broadening reach molecular diagnostics and improving patient access to precision oncology. In parallel, drug development discovery pipelines continue evolve, driving targeted therapeutic options forward. Yet, not all patients harboring actionable alterations respond these interventions, existing therapies do cover entire spectrum potential targets. this review, we examine current suite omics technologies employed clinical settings underscore their roles deepening our understanding biology optimizing stratification treatments. We also highlight relevant trials share own experiences using multi-omics data within board framework. Finally, discuss areas future exploration aimed at propelling new heights.

Язык: Английский

Процитировано

0
Inhibition of GCN2 Reveals Synergy with Cell-Cycle Regulation and Proteostasis DOI Creative Commons
Gregory Gauthier-Coles, Farid Rahimi,

Angelika Bröer

и другие.

Metabolites, Год журнала: 2023, Номер 13(10), С. 1064 - 1064

Опубликована: Окт. 9, 2023

The integrated stress response is a signaling network comprising four branches, each sensing different cellular stressors, converging on the phosphorylation of eIF2α to downregulate global translation and initiate recovery. One these branches includes GCN2, which senses amino acid insufficiency participates in maintaining homeostasis. Previous studies have shown that GCN2 viable cancer target when induced by inhibiting an additional target. In this light, we screened numerous drugs for their potential synergize with inhibitor TAP20. drug sensitivity six cell lines panel 25 compounds was assessed. Each compound then combined TAP20 at concentrations below IC50, impact growth evaluated. strongly synergistic combinations were further characterized using synergy analyses matrix-dependent invasion assays. Inhibitors proteostasis MEK-ERK pathway, as well pan-CDK inhibitors, flavopiridol, seliciclib, potently two lines. Among common CDK targets CDK7, more selectively targeted THZ-1 synergized Moreover, partially assessed However, alone sufficient restrict its growth-inhibitory IC50. We conclude inhibition can be explored vivo

Язык: Английский

Процитировано

4
Innovative strategies for measuring kinase activity to accelerate the next wave of novel kinase inhibitors DOI Creative Commons
Tim S. Veth,

Nynke M. Kannegieter,

Erik L. de Graaf

и другие.

Drug Discovery Today, Год журнала: 2024, Номер 29(3), С. 103907 - 103907

Опубликована: Янв. 30, 2024

The development of protein kinase inhibitors (PKIs) has gained significance owing to their therapeutic potential for diseases like cancer. In addition, there been a rise in refining activity assays, each possessing unique biological and analytical characteristics crucial PKI development. However, the pipeline experiences high attrition rates approved PKIs exhibit unexploited because variable patient responses. Enhancing efficiency involves addressing challenges related understanding mechanism action employing biomarkers precision medicine. Selecting appropriate assays these can overcome rate issues. This review delves into current obstacles inhibitor elucidates that provide solutions. Teaser: Kinase hold accelerate effective by multitude challenges. Here, we explore how solve improve

Язык: Английский

Процитировано

1