PLXNA1 confers enzalutamide resistance in prostate cancer via AKT signaling pathway
Although targeting the androgen signaling pathway by androgen receptor (AR) inhibitors, including enzalutamide, has shown therapeutic effectiveness, inevitable emergence of acquired resistance remains a critical challenge in the treatment of advanced prostate cancer (PCa). Recognizing targetable genomic aberrations that trigger endocrine treatment failure holds great promise for advancing therapeutic interventions. Here, we characterized PLXNA1, amplified in a subset of PCa patients, as a contributor to enzalutamide resistance (ENZR). Elevated PLXNA1 expression facilitated PCa proliferation under enzalutamide treatment due to AKT signaling activation. Mechanistically, PLXNA1 recruited NRP1 forming a PLXNA1-NRP1 complex, which in turn potentiated the phosphorylation of the AKT. Either inhibiting PLXNA1-NRP1 complex with an NRP1 inhibitor, EG01377, or targeting PLXNA1-mediated ENZR with AKT inhibitors, abolished the pro-resistance phenotype of PLXNA1. Taken together, combination of AKT inhibitor and AR inhibitors presents a promising therapeutic strategy for PCa, especially in advanced PCa patients exhibiting PLXNA1 overexpression.
Authors
- Baokai Dou
- Tingting Feng (ORCID: https://orcid.org/0000-0002-7281-8827)
- Hui Liu (ORCID: https://orcid.org/0000-0002-3481-1536)
- Bo Han (ORCID: https://orcid.org/0000-0003-4966-1398)
- Jing Zhang (ORCID: https://orcid.org/0000-0002-2702-1480)
- Lin Zhang (ORCID: https://orcid.org/0000-0001-5684-2555)
- Weiwen Chen (ORCID: https://orcid.org/0000-0003-4940-7445)
- Jing Hu (ORCID: https://orcid.org/0000-0001-7604-6732)
- Feifei Sun (ORCID: https://orcid.org/0000-0001-9304-0244)
- Ying Qu (ORCID: https://orcid.org/0009-0008-7259-1029)
- Lin Gao (ORCID: https://orcid.org/0000-0002-6913-2410)
- Jingying Han
- Qian Zhang (ORCID: https://orcid.org/0000-0002-1555-0860)
- Zeyuan Yu (ORCID: https://orcid.org/0000-0002-7814-5416)
Institutions
- Binzhou Medical University (CN)
- Shandong University of Aeronautics (CN)
- Shandong University (CN)
- Peking University (CN)
- Ningbo Center for Disease Control and Prevention (CN)
- Second Hospital of Shandong University (CN)
- Shandong Provincial Hospital (CN)
- Michigan Center for Translational Pathology (US)
- Peking University People's Hospital (CN)
- Qilu Hospital of Shandong University (CN)
- Shandong First Medical University (CN)
Publication Details
- Journal
- Neoplasia
- Published
- 2024-09-02
- DOI
- https://doi.org/10.1016/j.neo.2024.101047
- Citations
- 7
- Primary Topic
- Prostate Cancer Treatment and Research
- Type
- article
- Field-Weighted Citation Impact
- 2.93