Dual inhibition of MEK and PI3Kβ/δ-a potential therapeutic strategy in PTEN-wild-type docetaxel-resistant metastatic prostate cancer

• Main Authors: Vicenç Ruiz de Porras (Author), Adrià Bernat-Peguera (Author), Clara Alcon (Author), Fernando Laguia (Author), Maria Fernández-Saorin (Author), Natalia Jiménez (Author), Ana Senan-Salinas (Author), Carme Solé-Blanch (Author), Andrea Feu (Author), Mercedes Marín-Aguilera (Author), Juan Carlos Pardo (Author), Maria Ochoa- (Author), Joan Montero (Author), Begoña Mellado (Author), Albert Font (Author)
• Format: Book
• Published: Frontiers Media S.A., 2024-01-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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.

Item Description

1663-9812
10.3389/fphar.2024.1331648