ArticleEBioMedicine2015
PP2AC Level Determines Differential Programming of p38-TSC-mTOR Signaling and Therapeutic Response to p38-Targeted Therapy in Colorectal Cancer.
Article in EBioMedicine, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 26 citations in OpenAlex.
- Comprehensive analysis of telomere and aging-related signature for predicting prognosis and immunotherapy response in lung adenocarcinoma.Journal of cardiothoracic surgery · 2025Article
- cNEK6 induces gemcitabine resistance by promoting glycolysis in pancreatic ductal adenocarcinoma via the SNRPA/PPA2c/mTORC1 axis.Cell death & disease · 2024Article
- Oscillatory ERK Signaling and Morphology Determine Heterogeneity of Breast Cancer Cell Chemotaxis via MEK-ERK and p38-MAPK Signaling Pathways.Bioengineering (Basel, Switzerland) · 2023Article
- Patient-derived xenograft model in colorectal cancer basic and translational research.Animal models and experimental medicine · 2023Review
- Computational modeling implicates protein scaffolding in p38 regulation of Akt.Journal of theoretical biology · 2022Article
- Visual barcodes for clonal-multiplexing of live microscopy-based assays.Nature communications · 2022Article
- Article
- Diversity and versatility of p38 kinase signalling in health and disease.Nature reviews. Molecular cell biology · 2021Review
- Amino acids-Rab1A-mTORC1 signaling controls whole-body glucose homeostasis.Cell reports · 2021Article
- Article
- Ribosomal S6 protein kinase 4 promotes radioresistance in esophageal squamous cell carcinoma.The Journal of clinical investigation · 2020Article
- Article
- The p38 MAPK Signaling Activation in Colorectal Cancer upon Therapeutic Treatments.International journal of molecular sciences · 2020Review
- Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity.International journal of molecular sciences · 2020Review
- Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials.Science translational medicine · 2019Article
- Emerging Role of MicroRNAs in mTOR Signaling.Cellular and molecular life sciences : CMLS · 2017Review
- Identification of mechanically regulated phosphorylation sites on tuberin (TSC2) that control mechanistic target of rapamycin (mTOR) signaling.The Journal of biological chemistry · 2017Article
- Article
- PP2A Level in Colorectal Cancer Cells Predicts the Response of p38 Targeted Therapy.EBioMedicine · 2015Article
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
The p38 MAP kinase is a promising cancer drug target but its therapeutic effect is not fully understood. Here we report that the response of colorectal cancer (CRC) to p38 inhibitors (p38i) is highly variable: while p38i induces regression of one subgroup of CRCs, it stimulates growth of another subgroup. We further show that PP2AC is differentially expressed in the two different CRC subgroups, which determines the programing of p38-TSC-mTORC1 signaling through differential TSC2 phosphorylation at S664, 1254 and 1798, and the antitumor activity by p38i. Remarkably, modulation of PP2AC level is sufficient to reprogram p38-to-mTORC1 signaling and antitumor response. PP2AC expression accurately predicts therapeutic response to p38i in several CRC models, including a large cohort of patient-derived xenografts (PDXs). Moreover, we demonstrate that combination of p38 and mTOR kinase inhibitors effectively overcomes resistance to either inhibitor in single agent therapy. These results demonstrate that alternative routing of signal transduction underlies differential response to p38 and mTOR targeted therapies. The biomarker-guided therapeutic strategies described herein provide a compelling reason for testing in metastatic CRC patients who suffer very poor prognosis due to lack of efficacious drug therapies.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.