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The PPP2R1A cancer hotspot mutant p.R183W increases clofarabine resistance in uterine serous carcinoma cells by a gain-of-function mechanism.
Remmerie, Michiel; Dok, Rüveyda; Wang, Zhigang; Omella, Judit Domènech; Alen, Sophie; Cokelaere, Célie; Lenaerts, Lisa; Dreesen, Erwin; Nuyts, Sandra; Derua, Rita; Janssens, Veerle.
Afiliación
  • Remmerie M; Laboratory 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.
  • Dok R; KU Leuven Cancer Institute (LKI), Leuven, B-3000, Belgium.
  • Wang Z; KU Leuven Cancer Institute (LKI), Leuven, B-3000, Belgium.
  • Omella JD; Laboratory of Experimental Radiotherapy, Department of Oncology, University of Leuven (KU Leuven), Leuven, B-3000, Belgium.
  • Alen S; Clinical Pharmacology and Pharmacotherapy, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven (KU Leuven), Leuven, B-3000, Belgium.
  • Cokelaere C; Laboratory 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.
  • Lenaerts L; KU Leuven Cancer Institute (LKI), Leuven, B-3000, Belgium.
  • Dreesen E; Laboratory 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.
  • Nuyts S; Laboratory 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.
  • Derua R; KU Leuven Cancer Institute (LKI), Leuven, B-3000, Belgium.
  • Janssens V; Laboratory 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.
Cell Oncol (Dordr) ; 47(5): 1811-1829, 2024 Oct.
Article en En | MEDLINE | ID: mdl-38888850
ABSTRACT

PURPOSE:

Uterine 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

RESULTS:

USC 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.

CONCLUSIONS:

While 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Uterinas / Nucleótidos de Adenina / Cistadenocarcinoma Seroso / Resistencia a Antineoplásicos / Proteína Fosfatasa 2 / Clofarabina / Mutación Límite: Female / Humans Idioma: En Revista: Cell Oncol (Dordr) Año: 2024 Tipo del documento: Article País de afiliación: Bélgica Pais de publicación: Países Bajos
Texto completo
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PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Uterinas / Nucleótidos de Adenina / Cistadenocarcinoma Seroso / Resistencia a Antineoplásicos / Proteína Fosfatasa 2 / Clofarabina / Mutación Límite: Female / Humans Idioma: En Revista: Cell Oncol (Dordr) Año: 2024 Tipo del documento: Article País de afiliación: Bélgica Pais de publicación: Países Bajos