ArticleMolecular cancer therapeutics2016
Quantitative Phosphoproteomics Reveals Wee1 Kinase as a Therapeutic Target in a Model of Proneural Glioblastoma.
Article in Molecular cancer therapeutics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers, 1 of them a synthesis that pooled it.
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Who cites it
23 citing papers in PubMed, 1 synthesis or guideline pooled it, 38 citations in OpenAlex.
- Systematic Review of Molecular Targeted Therapies for Adult-Type Diffuse Glioma: An Analysis of Clinical and Laboratory Studies.International journal of molecular sciences · 2023Pooled it
- Article
- Integration of transcriptomics, proteomics and loss-of-function screening reveals WEE1 as a target for combination with dasatinib against proneural glioblastoma.Cancer letters · 2024Article
- Comprehensive understanding of glioblastoma molecular phenotypes: classification, characteristics, and transition.Cancer biology & medicine · 2024Review
- Genome-wide CRISPR screens identify PKMYT1 as a therapeutic target in pancreatic ductal adenocarcinoma.EMBO molecular medicine · 2024Article
- Molecular Targeted Therapies in Glioblastoma Multiforme: A Systematic Overview of Global Trends and Findings.Brain sciences · 2023Review
- Different Approaches for the Profiling of Cancer Pathway-Related Genes in Glioblastoma Cells.International journal of molecular sciences · 2022Article
- Phosphoproteomics of primary AML patient samples reveals rationale for AKT combination therapy and p53 context to overcome selinexor resistance.Cell reports · 2022Article
- Glioblastoma: Current Status, Emerging Targets, and Recent Advances.Journal of medicinal chemistry · 2022Review
- Enhancing anti-tumour innate immunity by targeting the DNA damage response and pattern recognition receptors in combination with radiotherapy.Frontiers in oncology · 2022Review
- Article
- A link between mitotic defects and mitotic catastrophe: detection and cell fate.Biology direct · 2021Review
- Quantitative Analysis of Tyrosine Phosphorylation from FFPE Tissues Reveals Patient-Specific Signaling Networks.Cancer research · 2021Article
- Identification of covalent modifications regulating immune signaling complex composition and phenotype.Molecular systems biology · 2021Article
- Overexpression of PKMYT1 Facilitates Tumor Development and Is Correlated with Poor Prognosis in Clear Cell Renal Cell Carcinoma.Medical science monitor : international medical journal of experimental and clinical research · 2020Article
- DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer.Signal transduction and targeted therapy · 2020Review
- Systematic expression analysis of WEE family kinases reveals the importance of PKMYT1 in breast carcinogenesis.Cell proliferation · 2020Article
- The DNA-damage response and nuclear events as regulators of nonapoptotic forms of cell death.Oncogene · 2020Review
- Wee1 Inhibitor AZD1775 Effectively Inhibits the Malignant Phenotypes of Esophageal Squamous Cell CarcinomaFrontiers in pharmacology · 2019Article
- Phosphoproteomics of Retinoblastoma: A Pilot Study Identifies Aberrant Kinases.Molecules (Basel, Switzerland) · 2018Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Glioblastoma (GBM) is the most common malignant primary brain cancer. With a median survival of about a year, new approaches to treating this disease are necessary. To identify signaling molecules regulating GBM progression in a genetically engineered murine model of proneural GBM, we quantified phosphotyrosine-mediated signaling using mass spectrometry. Oncogenic signals, including phosphorylated ERK MAPK, PI3K, and PDGFR, were found to be increased in the murine tumors relative to brain. Phosphorylation of CDK1 pY15, associated with the G2 arrest checkpoint, was identified as the most differentially phosphorylated site, with a 14-fold increase in phosphorylation in the tumors. To assess the role of this checkpoint as a potential therapeutic target, syngeneic primary cell lines derived from these tumors were treated with MK-1775, an inhibitor of Wee1, the kinase responsible for CDK1 Y15 phosphorylation. MK-1775 treatment led to mitotic catastrophe, as defined by increased DNA damage and cell death by apoptosis. To assess the extensibility of targeting Wee1/CDK1 in GBM, patient-derived xenograft (PDX) cell lines were also treated with MK-1775. Although the response was more heterogeneous, on-target Wee1 inhibition led to decreased CDK1 Y15 phosphorylation and increased DNA damage and apoptosis in each line. These results were also validated in vivo, where single-agent MK-1775 demonstrated an antitumor effect on a flank PDX tumor model, increasing mouse survival by 1.74-fold. This study highlights the ability of unbiased quantitative phosphoproteomics to reveal therapeutic targets in tumor models, and the potential for Wee1 inhibition as a treatment approach in preclinical models of GBM. Mol Cancer Ther; 15(6); 1332-43. ©2016 AACR.
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