Dual inhibition of MEK and PI3Kβ/δ-a potential therapeutic strategy in PTEN-wild-type docetaxel-resistant metastatic prostate cancer
Ruiz de Porras, Vicenç (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Bernat-Peguera, Adrià (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Alcon, Clara (Universitat de Barcelona)
Laguia, Fernando (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Fernández-Saorin, María (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Jiménez, Natalia (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Senan-Salinas, Ana (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Solé-Blanch, Carme (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Feu, Andrea (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Marín-Aguilera, Mercedes (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Pardo, Juan Carlos (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Ochoa-de-Olza, Maria (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Montero, Joan (Universitat de Barcelona)
Mellado, Begoña (Hospital Clínic i Provincial de Barcelona)
Font, Albert (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)

Data:	2024
Resum:	Background: Docetaxel remains the standard treatment for metastatic castration-resistant prostate cancer (mCRPC). However, resistance frequently emerges as a result of hyperactivation of the PI3K/AKT and the MEK/ERK pathways. Therefore, the inhibition of these pathways presents a potential therapeutic approach. In this study, we evaluated the efficacy of simultaneous inhibition of the PI3K/AKT and MEK/ERK pathways in docetaxel-resistant mCRPC, both in vitro and in vivo. Methods: Docetaxel-sensitive and docetaxel-resistant mCRPC cells were treated with selumetinib (MEK1/2 inhibitor), AZD8186 (PI3Kβ/δ inhibitor) and capivasertib (pan-AKT inhibitor) alone and in combination. Efficacy and toxicity of selumetinib+AZD8186 were tested in docetaxel-resistant xenograft mice. CRISPR-Cas9 generated a PTEN-knockdown docetaxel-resistant cell model. Changes in phosphorylation of AKT, ERK and downstream targets were analyzed by Western blot. Antiapoptotic adaptations after treatments were detected by dynamic BH3 profiling. Results: PI3K/AKT and MEK/ERK pathways were hyperactivated in PTEN-wild-type (wt) docetaxel-resistant cells. Selumetinib+AZD8186 decreased cell proliferation and increased apoptosis in PTEN-wt docetaxel-resistant cells. This observation was further confirmed in vivo, where docetaxel-resistant xenograft mice treated with selumetinib+AZD8186 exhibited reduced tumor growth without additional toxicity. Conclusion: Our findings on the activity of selumetinib+AZD8186 in PTEN-wt cells and in docetaxel-resistant xenograft mice provide an excellent rationale for a novel therapeutic strategy for PTEN-wt mCRPC patients resistant to docetaxel, in whom, unlike PTEN-loss patients, a clinical benefit of treatment with single-agent PI3K and AKT inhibitors has not been demonstrated. A phase I-II trial of this promising combination is warranted.
Nota:	Altres ajuts: Astra Zeneca Farmacéutica Spain S.A. (NCR-17-13419)
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Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	AZD8186 ; Selumetinib ; Metastatic castration-resistant prostate cancer ; PTEN status ; Taxane resistance
Publicat a:	Frontiers in Pharmacology, Vol. 15 (January 2024) , ISSN 1663-9812

DOI: 10.3389/fphar.2024.1331648
PMID: 38318136

12 p, 2.8 MB

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Documents de recerca > Documents dels grups de recerca de la UAB > Centres i grups de recerca (producció científica) > Ciències de la salut i biociències > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
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