Evidence map›Paper›PMID 38888850›Full record

ArticleCellular oncology (Dordrecht, Netherlands)2024

The PPP2R1A cancer hotspot mutant p.R183W increases clofarabine resistance in uterine serous carcinoma cells by a gain-of-function mechanism.

Michiel Remmerie, Rüveyda Dok, Zhigang Wang, Judit Domènech Omella, Sophie Alen, Célie Cokelaere, Lisa Lenaerts, Erwin Dreesen, Sandra Nuyts, Rita Derua and 1 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cellular oncology (Dordrecht, Netherlands), 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

5 citing papers in PubMed.

  1. Review
  2. Review
  3. Houge-Janssens syndrome.European journal of human genetics : EJHG · 2025
    Review
  4. Silencing PPP2R1A inhibits the progression of gastric cancer cells.Journal of cancer research and clinical oncology · 2025
    Article
  5. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors.

Michiel RemmerieLaboratory of Protein Phosphorylation and Proteomics, Department of Cellular and Molecular Medicine, University of Leuven (KU Leuven), Gasthuisberg O&N1, Herestraat 49, PO-box 901, Leuven, B-3000, Belgium.
Rüveyda DokKU Leuven Cancer Institute (LKI), Leuven, B-3000, Belgium.
Zhigang WangClinical Pharmacology and Pharmacotherapy, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven (KU Leuven), Leuven, B-3000, Belgium.
Judit Domènech OmellaLaboratory of Protein Phosphorylation and Proteomics, Department of Cellular and Molecular Medicine, University of Leuven (KU Leuven), Gasthuisberg O&N1, Herestraat 49, PO-box 901, Leuven, B-3000, Belgium.
Sophie AlenLaboratory of Protein Phosphorylation and Proteomics, Department of Cellular and Molecular Medicine, University of Leuven (KU Leuven), Gasthuisberg O&N1, Herestraat 49, PO-box 901, Leuven, B-3000, Belgium.
Célie CokelaereLaboratory of Protein Phosphorylation and Proteomics, Department of Cellular and Molecular Medicine, University of Leuven (KU Leuven), Gasthuisberg O&N1, Herestraat 49, PO-box 901, Leuven, B-3000, Belgium.
Lisa LenaertsLaboratory of Protein Phosphorylation and Proteomics, Department of Cellular and Molecular Medicine, University of Leuven (KU Leuven), Gasthuisberg O&N1, Herestraat 49, PO-box 901, Leuven, B-3000, Belgium.
Erwin DreesenClinical Pharmacology and Pharmacotherapy, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven (KU Leuven), Leuven, B-3000, Belgium.
Sandra NuytsKU Leuven Cancer Institute (LKI), Leuven, B-3000, Belgium.
Rita DeruaLaboratory of Protein Phosphorylation and Proteomics, Department of Cellular and Molecular Medicine, University of Leuven (KU Leuven), Gasthuisberg O&N1, Herestraat 49, PO-box 901, Leuven, B-3000, Belgium.
Veerle JanssensLaboratory of Protein Phosphorylation and Proteomics, Department of Cellular and Molecular Medicine, University of Leuven (KU Leuven), Gasthuisberg O&N1, Herestraat 49, PO-box 901, Leuven, B-3000, Belgium. veerle.janssens@kuleuven.be.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

purposeUterine serous carcinoma (USC) is generally associated with poor prognosis due to a high recurrence rate and frequent treatment resistance; hence, there is a need for improved therapeutic strategies. Molecular analysis of USC identified several molecular markers, useful to improve current treatments or identify new druggable targets. PPP2R1A, encoding the Aα subunit of the tumor suppressive Ser/Thr phosphatase PP2A, is mutated in up to 40% of USCs. Here, we investigated the effect of the p.R183W PPP2R1A hotspot variant on treatment response to the nucleoside analogue clofarabine. METHODS AND

resultsUSC cells stably expressing p.R183W Aα showed increased resistance to clofarabine treatment in vitro and, corroborated by decreased clofarabine-induced apoptosis, G1 phase arrest, DNA-damage (γH2AX) and activation of ATM and Chk1/2 kinases. Phenotypic rescue by pharmacologic PP2A inhibition or dicer-substrate siRNA (dsiRNA)-mediated B56δ subunit knockdown supported a gain-of-function mechanism of Aα p.R183W, promoting dephosphorylation and inactivation of deoxycytidine kinase (dCK), the cellular enzyme responsible for the conversion of clofarabine into its bioactive form. Therapeutic assessment of related nucleoside analogues (gemcitabine, cladribine) revealed similar effects, but in a cell line-dependent manner. Expression of two other PPP2R1A USC mutants (p.P179R or p.S256F) did not affect clofarabine response in our cell models, arguing for mutant-specific effects on treatment outcome as well.

conclusionsWhile our results call for PPP2R1A mutant and context-dependent effects upon clofarabine/nucleoside analogue monotherapy, combining clofarabine with a pharmacologic PP2A inhibitor proved synergistically in all tested conditions, highlighting a new generally applicable strategy to improve treatment outcome in USC.

Indexed as

Adenine NucleotidesClofarabineCystadenocarcinoma, SerousDrug Resistance, NeoplasmMutationProtein Phosphatase 2Uterine NeoplasmsApoptosisArabinonucleosidesCell Line, TumorFemaleHumansAdenine NucleotidesArabinonucleosidesClofarabinePPP2R1A protein, humanProtein Phosphatase 2Deoxycytidine kinase (dCK)Gain-of-function (GOF) mutationNucleoside analoguePPP2R1AProtein phosphatase 2A (PP2A)Uterine serous carcinoma (USC)

Identifiers

PMID38888850
PMCPMC12973965

What OpenQuestion holds

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Registered trials

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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.