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.
Frontiers in pharmacology. 2024 Jan 22*** epublish ***
Vicenç Ruiz de Porras, Adrià Bernat-Peguera, Clara Alcon, Fernando Laguia, Maria Fernández-Saorin, Natalia Jiménez, Ana Senan-Salinas, Carme Solé-Blanch, Andrea Feu, Mercedes Marín-Aguilera, Juan Carlos Pardo, Maria Ochoa-de-Olza, Joan Montero, Begoña Mellado, Albert Font
CARE Program, Germans Trias i Pujol Research Institute (IGTP), Badalona, Barcelona, Spain., Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain., IrsiCaixa AIDS Research Institute, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain., Translational Genomics and Targeted Therapeutics in Solid Tumors Lab, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), Barcelona, Spain., Department of Pathology, Germans Trias i Pujol University Hospital, Badalona, Barcelona, Spain.