ArticleBritish journal of cancer2014
Mutant PIK3CA controls DUSP1-dependent ERK 1/2 activity to confer response to AKT target therapy.
Article in British journal of cancer, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 36 citations in OpenAlex.
- Article
- Dual-Specificity Protein Phosphatases Targeting Extracellular Signal-Regulated Kinases: Friends or Foes in the Biology of Cancer?International journal of molecular sciences · 2025Review
- Emerging molecular therapies in the treatment of bladder cancer.Exploration of targeted anti-tumor therapy · 2024Review
- Landscape of targeted therapies for advanced urothelial carcinoma.Exploration of targeted anti-tumor therapy · 2024Review
- A Three-Gene Signature Predicts Response to Selinexor in Multiple Myeloma.JCO precision oncology · 2022Article
- Emerging Roles for Mammalian Target of Rapamycin (mTOR) Complexes in Bladder Cancer Progression and Therapy.Cancers · 2022Review
- Dual-specificity phosphatases: therapeutic targets in cancer therapy resistance.Journal of cancer research and clinical oncology · 2022Review
- DUSP7 inhibits cervical cancer progression by inactivating the RAS pathway.Journal of cellular and molecular medicine · 2021Article
- Human cathelicidin antimicrobial peptide LL-37 promotes lymphangiogenesis in lymphatic endothelial cells through the ERK and Akt signaling pathways.Molecular biology reports · 2020Article
- Synergistic Effects of Combination Therapy with AKT and mTOR Inhibitors on Bladder Cancer Cells.International journal of molecular sciences · 2020Article
- PIK3CA Is Regulated by CUX1, Promotes Cell Growth and Metastasis in Bladder CancerFrontiers in oncology · 2020Article
- Establishment of xenografts of urological cancers on chicken chorioallantoic membrane (CAM) to study metastasis.Precision clinical medicine · 2019Article
- Dual Inhibition of Pirarubicin-InducedFrontiers in pharmacology · 2019Article
- Association between single nucleotide polymorphisms in the PI3K/AKT/mTOR pathway and bladder cancer risk in a sample of Iranian population.EXCLI journal · 2018Article
- Downregulation ofJournal of Cancer · 2018Article
- Parallel PI3K, AKT and mTOR inhibition is required to control feedback loops that limit tumor therapy.PloS one · 2018Article
- Gefitinib enhances sensitivity of endometrial cancer cells to progestin therapy via dual-specificity phosphatase 1.Oncotarget · 2017Article
- The Phosphatidylinositol 3-Kinase Pathway as a Potential Therapeutic Target in Bladder Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2017Article
- PIK3CA dependence and sensitivity to therapeutic targeting in urothelial carcinoma.BMC cancer · 2016Article
- [Report on the 5th symposium of the German research network bladder carcinoma].Der Urologe. Ausg. A · 2016Article
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundAlterations in the phosphoinositide 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) signalling pathway are frequent in urothelial bladder cancer (BLCA) and thus provide a potential target for novel therapeutic strategies. We investigated the efficacy of the AKT inhibitor MK-2206 in BLCA and the molecular determinants that predict therapy response.
methodsBiochemical and functional effects of the AKT inhibitor MK-2206 were analysed on a panel of 11 BLCA cell lines possessing different genetic alterations. Cell viability (CellTiter-Blue, cell counts), apoptosis (caspase 3/7 activity) and cell cycle progression (EdU incorporation) were analysed to determine effects on cell growth and proliferation. cDNA or siRNA transfections were used to manipulate the expression of specific proteins such as wild-type or mutant PIK3CA, DUSP1 or CREB. For in vivo analysis, the chicken chorioallantoic membrane model was utilised and tumours were characterised by weight and biochemically for the expression of Ki-67 and AKT phosphorylation.
resultsTreatment with MK-2206 suppressed AKT and S6K1 but not 4E-BP1 phosphorylation in all cell lines. Functionally, only cell lines bearing mutations in the hotspot helical domain of PIK3CA were sensitive to the drug, independent of other genetic alterations in the PI3K or MAPK signalling pathway. Following MK-2206 treatment, the presence of mutant PIK3CA resulted in an increase in DUSP1 expression that induced a decrease in ERK 1/2 phosphorylation. Manipulating the expression of mutant or wild-type PIK3CA or DUSP1 confirmed that this mechanism is responsible for the induction of apoptosis and the inhibition of tumour proliferation in vitro and in vivo, to sensitise cells to AKT target therapy.Conclusion or interpretation:PIK3CA mutations confer sensitivity to AKT target therapy in BLCA by regulating DUSP1 expression and subsequent ERK1/2 dephosphorylation and can potentially serve as a stratifying biomarker for treatment.
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